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  • 1.
    Abu-Siniyeh, Ahmed
    et al.
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Owen, Dylan M.
    Kings Coll London, Dept Phys, London WC2R 2LS, England.;Kings Coll London, Randall Div Cell & Mol Biophys, London WC2R 2LS, England..
    Benzing, Carola
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Rinkwitz, Silke
    Becker, Thomas S.
    Univ Sydney, Brain & Mind Res Inst, Sydney Med Sch, Sydney, NSW 2006, Australia.;Univ Sydney, Dept Hlth Sci, Sydney, NSW 2006, Australia..
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gaus, Katharina
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis2016In: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 17, no 1, p. 66-79Article in journal (Refereed)
    Abstract [en]

    The differential distribution of lipids between apical and basolateral membranes is necessary for many epithelial cell functions, but how this characteristic membrane organization is integrated within the polarity network during ductal organ development is poorly understood. Here we quantified membrane order in the gut, kidney and liver ductal epithelia in zebrafish larvae at 3-11 days post fertilization (dpf) with Laurdan 2-photon microscopy. We then applied a combination of Laurdan imaging, antisense knock-down and analysis of polarity markers to understand the relationship between membrane order and apical-basal polarity. We found a reciprocal relationship between membrane order and the cell polarity network. Reducing membrane condensation by exogenously added oxysterol or depletion of cholesterol reduced apical targeting of the polarity protein, aPKC. Conversely, using morpholino knock down in zebrafish, we found that membrane order was dependent upon the Crb3 and Par3 polarity protein expression in ductal epithelia. Hence our data suggest that the biophysical property of membrane lipid packing is a regulatory element in apical basal polarity.

  • 2.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, p. 7743-7748Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 3.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGFR alpha signaling is required for alveolar development in the mouse lung2017In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 145, p. S147-S147Article in journal (Other academic)
  • 4.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Leonor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gallini, Radiosa
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fredriksson, Linda
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Nilsson, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Johansson, Bengt R.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Electron Microscopy Unit, S-40530 Gothenburg, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex2016In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, no 4, p. 461-474Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.

  • 5.
    Aspelund, Aleksanteri
    et al.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Robciuc, Marius R.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Karaman, Sinem
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alitalo, Kari
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Lymphatic System in Cardiovascular Medicine2016In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 118, no 3, p. 515-530Article, review/survey (Refereed)
    Abstract [en]

    The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.

  • 6. Aspelund, Aleksanteri
    et al.
    Tammela, Tuomas
    Antila, Salli
    Nurmi, Harri
    Leppanen, Veli-Matti
    Zarkada, Georgia
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    Therapeutic Insights to Lymphangiogenic Growth Factors2015In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, no S1, p. 19-19Article in journal (Other academic)
  • 7.
    Bartlett, Christina S.
    et al.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Quaggin, Susan E.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Vascular Growth Factors and Glomerular Disease2016In: ANNUAL REVIEW OF PHYSIOLOGY, VOL 78, ANNUAL REVIEWS, 2016, p. 437-461Chapter in book (Refereed)
    Abstract [en]

    The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier. VEGF, ANGPT, EGF, SEMA3A, TGF-beta, and CXCL12 signal in paracrine fashions between the podocytes, endothelium, and mesangium associated with the glomerular capillary bed to maintain filtration barrier function. In this review, we summarize the current understanding of these signaling pathways in the development and maintenance of the glomerulus and the progression of disease.

  • 8.
    Bentley, Katie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    The temporal basis of angiogenesis2017In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 372, no 1720, p. 1-11, article id 20150522Article in journal (Refereed)
    Abstract [en]

    The process of new blood vessel growth (angiogenesis) is highly dynamic, involving complex coordination of multiple cell types. Though the process must carefully unfold over time to generate functional, well-adapted branching networks, we seldom hear about the time-based properties of angiogenesis, despite timing being central to other areas of biology. Here, we present a novel, time-based formulation of endothelial cell behaviour during angiogenesis and discuss a flurry of our recent, integrated in silico/in vivo studies, put in context to the wider literature, which demonstrate that tissue conditions can locally adapt the timing of collective cell behaviours/decisions to grow different vascular network architectures. A growing array of seemingly unrelated 'temporal regulators' have recently been uncovered, including tissue derived factors (e.g. semaphorins or the high levels of VEGF found in cancer) and cellular processes (e.g. asymmetric cell division or filopodia extension) that act to alter the speed of cellular decisions to migrate. We will argue that 'temporal adaptation' provides a novel account of organ/disease-specific vascular morphology and reveals 'timing' as a new target for therapeutics. We therefore propose and explain a conceptual shift towards a 'temporal adaptation' perspective in vascular biology, and indeed other areas of biology where timing remains elusive. This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.

  • 9.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, AZ ICMC, Huddinge, Sweden.
    Cell-cell signaling in blood vessel development and function2018In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 10, no 3, article id UNSP e8610Article in journal (Other academic)
    Abstract [en]

    The blood vasculature is an organ pervading all other organs (almost). During vascular development, cell-cell signaling by extracellular ligands and cell surface receptors ensure that new vessels sprout into non-vascularized regions and simultaneously acquire organ-specific specializations and adaptations that match the local physiological needs. The vessels thereby specialize in their permeability, molecular transport between blood and tissue, and ability to regulate blood flow on demand. Over the past decades, we have learnt about the generic cell-cell signaling mechanisms governing angiogenic sprouting, mural cell recruitment, and vascular remodeling, and we have obtained the first insights into signals that induce and maintain vascular organotypicity. However, intra-organ vascular diversity and arterio-venous hierarchies complicate the molecular characterization of the vasculature's cellular building blocks. Single-cell RNA sequencing provides a way forward, as it allows elucidation at a genome-wide and quantitative level of the transcriptional diversity occurring within the same cell types at different anatomical positions and levels of arterio-venous hierarchy in the organs. In this Louis-Jeantet Prize Winner: Commentary, I give a brief overview of vascular development and how recent advances in the field pave the way for more systematic efforts to explore vascular functions in health and disease.

  • 10.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lipid transport and human brain development2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 7, p. 699-701Article in journal (Other academic)
    Abstract [en]

    How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.

  • 11.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Transcriptional control of endothelial energy2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 529, no 7585, p. 160-161Article in journal (Other academic)
  • 12. Bianchi, Roberta
    et al.
    Teijeira, Alvaro
    Proulx, Steven T.
    Christiansen, Ailsa J.
    Seidel, Catharina D.
    Ruelicke, Thomas
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Haegerling, Rene
    Halin, Cornelia
    Detmar, Michael
    A Transgenic Prox1-Cre-tdTomato Reporter Mouse for Lymphatic Vessel Research2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0122976Article in journal (Refereed)
    Abstract [en]

    The lymphatic vascular system plays an active role in immune cell trafficking, inflammation and cancer spread. In order to provide an in vivo tool to improve our understanding of lymphatic vessel function in physiological and pathological conditions, we generated and characterized a tdTomato reporter mouse and crossed it with a mouse line expressing Cre recombinase under the control of the lymphatic specific promoter Prox1 in an inducible fashion. We found that the tdTomato fluorescent signal recapitulates the expression pattern of Prox1 in lymphatic vessels and other known Prox1-expressing organs. Importantly, tdTomato co-localized with the lymphatic markers Prox1, LYVE-1 and podoplanin as assessed by whole-mount immunofluorescence and FACS analysis. The tdTomato reporter was brighter than a previously established red fluorescent reporter line. We confirmed the applicability of this animal model to intravital microscopy of dendritic cell migration into and within lymphatic vessels, and to fluorescence-activated single cell analysis of lymphatic endothelial cells. Additionally, we were able to describe the early morphological changes of the lymphatic vasculature upon induction of skin inflammation. The Prox1-Cre-tdTomato reporter mouse thus shows great potential for lymphatic research.

  • 13. Bravi, Luca
    et al.
    Rudini, Noemi
    Cuttano, Roberto
    Giampietro, Costanza
    Maddaluno, Luigi
    Ferrarini, Luca
    Adams, Ralf H.
    Corada, Monica
    Boulday, Gwenola
    Tournier-Lasserve, Elizabeth
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lampugnani, Maria Grazia
    Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 27, p. 8421-8426Article in journal (Refereed)
    Abstract [en]

    Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-beta/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate beta-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

  • 14.
    Caolo, V.
    et al.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Peacock, H. M.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Kasaai, B.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Swennen, G.
    Maastricht Univ, CARIM, Maastricht, Netherlands..
    Gordon, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Verhamme, P.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Jones, E. A. V.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Shear stress, notch and VE-cadherin: the molecular mechanism of vascular fusion2018In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S13-S13Article in journal (Other academic)
  • 15.
    Caolo, Vincenza
    et al.
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Peacock, Hanna M.
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Kasaai, Bahar
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Swennen, Geertje
    Maastricht Univ, CARIM, Dept Physiol, Maastricht, Netherlands.
    Gordon, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Post, Mark J.
    Maastricht Univ, CARIM, Dept Physiol, Maastricht, Netherlands.
    Verhamme, Peter
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Jones, Elizabeth A. V.
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Shear Stress and VE-Cadherin: The Molecular Mechanism of Vascular Fusion2018In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 9, p. 2174-2183Article in journal (Refereed)
    Abstract [en]

    Objective: Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion.

    Approach and Results: We previously showed that both low shear stress and DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion.

    Conclusions: This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.

  • 16.
    Carthy, Jon M.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Imperial Coll London, Fac Med, Div Brain Sci, London, England..
    Stoeter, Martin
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Bellomo, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Angelos
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moren, Anita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Kardassis, Dimitris
    Univ Crete, Sch Med, Dept Biochem, Iraklion 71003, Crete, Greece..
    Gahman, Timothy C.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Shiau, Andrew K.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Bickle, Marc
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Zerial, Marino
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 29868Article in journal (Refereed)
    Abstract [en]

    Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

  • 17.
    Carvalho, Alexandra T. P.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Gouveia, Leonor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kanna, Charan Raju
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Warmlander, Sebastian K. T. S.
    Platts, Jamie A.
    Kamerlin, Lynn Shina Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation2014In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 12, p. 1604-1612Article in journal (Refereed)
    Abstract [en]

    We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.

  • 18.
    Castro, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Álvarez-Aznar, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brakebusch, Cord
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. AstraZeneca/Karolinska Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expressionManuscript (preprint) (Other academic)
  • 19.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tumor-Induced Local and Systemic Impact on Blood Vessel Function2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 418290Article, review/survey (Refereed)
    Abstract [en]

    Endothelial dysfunction plays a role in several processes that contribute to cancer-associated mortality. The vessel wall serves as a barrier for metastatic tumor cells, and the integrity and activation status of the endothelium serves as an important defense mechanism against metastasis. In addition, leukocytes, such as cytotoxic T-cells, have to travel across the vessel wall to enter the tumor tissue where they contribute to killing of cancer cells. Tumor cells can alter the characteristics of the endothelium by recruitment of leukocytes such as neutrophils andmacrophages, which further stimulate inflammation and promote tumorigenesis. Recent findings also suggest that leukocyte-mediated effects on vascular function are not limited to the primary tumor or tissues that represent metastatic sites. Peripheral organs, such as kidney and heart, also display impaired vascular function in tumor-bearing individuals, potentially contributing to organ failure. Here, we discuss how vascular function is altered in malignant tissue and distant organs in individuals with cancer and how leukocytes function as potent mediators of these tumor-induced effects.

  • 20.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tumor-induced neutrophil extracellular traps-drivers of systemic inflammation and vascular dysfunction2016In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 3, article id e1098803Article in journal (Other academic)
    Abstract [en]

    Neutrophil extracellular traps (NETs) are part of the innate immune defense against microbes, but their contribution to several non-infectious inflammatory conditions has recently been unraveled. We demonstrate that NETs accumulate in the peripheral circulation in tumor-bearing mice, causing systemic inflammation and vascular dysfuntion in organs not affected by tumor cells.

  • 21.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Saupe, Falk
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Divis Family Med, Huddinge, Sweden.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed)
    Abstract [en]

    Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

  • 22.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Femel, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed)
    Abstract [en]

    Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

  • 23.
    Chiang, Ivy Kim-Ni
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Fritzsche, Martin
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Pichol-Thievend, Cathy
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Neal, Alice
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Holmes, Kelly
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Lagendijk, Anne
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Overman, Jeroen
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    D'Angelo, Donatella
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Omini, Alice
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Hermkens, Dorien
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Lesieur, Emmanuelle
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Liu, Ke
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Ratnayaka, Indrika
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Corada, Monica
    FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy..
    Bou-Gharios, George
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Carroll, Jason
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy.
    Schulte-Merker, Stefan
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Hogan, Benjamin
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Beltrame, Monica
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    De Val, Sarah
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Francois, Mathias
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development2017In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 14, p. 2629-2639Article in journal (Refereed)
    Abstract [en]

    Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancerswere able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo. Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

  • 24.
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alk1 (Activin Receptor-Like Kinase 1) and Vascular Hyperpermeability in Diabetic Retinopathy: More Is Less2018In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, no 8, p. 1673-1675Article in journal (Other academic)
  • 25.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    New Frontiers in VEGF/VEGFR Biology2015In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, p. 79-79Article in journal (Other academic)
  • 26.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    On the physiology of vascular permeability2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, p. 19-19Article in journal (Other academic)
  • 27.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vascular permeability - the essentials2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 135-143Article, review/survey (Refereed)
    Abstract [en]

    The vasculature, composed of vessels of different morphology and function, distributes blood to all tissues and maintains physiological tissue homeostasis. In pathologies, the vasculature is often affected by, and engaged in, the disease process. This may result in excessive formation of new, unstable, and hyperpermeable vessels with poor blood flow, which further promotes hypoxia and disease propagation. Chronic vessel permeability may also facilitate metastatic spread of cancer. Thus, there is a strong incentive to learn more about an important aspect of vessel biology in health and disease: the regulation of vessel permeability. The current review aims to summarize current insights into different mechanisms of vascular permeability, its regulatory factors, and the consequences for disease.

  • 28.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    VEGF receptor signal transduction - A brief update2016In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 86, p. 14-17Article, review/survey (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) signal transduction through receptor tyrosine lcinases VEGF receptor 1, -2 and -3 is of crucial importance for monocytes/macrophages, blood vascular endothelial and lymphatic endothelial cells both in physiology and in a number of pathologies notably cancer. This brief review summarizes the current status of VEGF receptor signaling with emphasis on in vivo data.

  • 29.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Royal Swedish Acad Sci, POB 50005, SE-10405 Stockholm, Sweden..
    Hansson, Goran K.
    Royal Swedish Acad Sci, POB 50005, SE-10405 Stockholm, Sweden..
    Tracheobronchial transplantation: The Royal Swedish Academy of Sciences' concerns2016In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 387, no 10022, p. 942-942Article in journal (Refereed)
  • 30. Collu, Giovanna M.
    et al.
    Jenny, Andreas
    Albert Einstein Coll Med, Dept Dev & Mol Biol, New York, NY USA;Albert Einstein Coll Med, Dept Genet, New York, NY USA.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mirkovic, Ivana
    Chin, Meiling
    Transon Asia Inc, Dayuan, Taoyuan County, Taiwan.
    Weber, Ursula
    Smith, Michael J.
    Mlodzik, Marek
    Icahn Sch Med Mt Sinai, Dept Cell Dev & Regenerat Biol, New York, NY 10029 USA.
    Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 5, article id e1007391Article in journal (Refereed)
    Abstract [en]

    Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The 'core' PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pk(pk) but not pk(sple) and enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate.

  • 31.
    Costa, Guilherme
    et al.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Harrington, Kyle I.
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Lovegrove, Holly E.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Page, Donna J.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Herbert, Shane P.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Asymmetric division coordinates collective cell migration in angiogenesis2016In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 18, no 12, p. 1292-+Article in journal (Refereed)
    Abstract [en]

    The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell division generates daughters of distinct size with discrete 'tip' or 'stalk' thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives Dll4/Notch-independent self-organization of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomizes daughter tip/stalk selection. Thus, asymmetric division seamlessly integrates cell proliferation with collective migration, and, as such, may facilitate growth of other collectively migrating tissues during development, regeneration and cancer invasion.

  • 32.
    Cruys, Bert
    et al.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Wong, Brian W.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Kuchnio, Anna
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Verdegem, Dries
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cantelmo, Anna Rita
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Conradi, Lena-Christin
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vandekeere, Saar
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bouche, Ann
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cornelissen, Ivo
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vinckier, Stefan
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Merks, Roeland M. H.
    Ctr Wiskunde & Informat, Life Sci Grp, Sci Pk 123, NL-1098 XG Amsterdam, Netherlands.;Leiden Univ, Math Inst, Niels Bohrweg 1, NL-2333 CA Leiden, Netherlands..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Via Adamello 16, I-20139 Milan, Italy.;Univ Milan, Dept Oncol & Hematooncol, I-20139 Milan, Italy..
    Gerhardt, Holger
    Katholieke Univ Leuven, Vasc Patterning Lab, Dept Oncol, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Vasc Patterning Lab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;Max Delbruck Ctr Mol Med, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany..
    Dewerchin, Mieke
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Dept Pathol, Computat Biol Lab, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA..
    Carmeliet, Peter
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Glycolytic regulation of cell rearrangement in angiogenesis2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12240Article in journal (Refereed)
    Abstract [en]

    During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases.

  • 33.
    Cunha, Sara I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jia, Min
    Karolinska Inst, Dept Biosci & Nutr, S-14157 Stockholm, Sweden.
    Souchelnytskyi, Serhiy
    Qatar Univ, Coll Med, Bldg H12,Al Jamiaa St, Doha 2713, Qatar.
    Exposure to EGF and 17 beta-estradiol irreversibly affects the proliferation and transformation of MCF7 cells but is not sufficient to promote tumor growth in a xenograft mouse model upon withdrawal of exposure2018In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 42, no 3, p. 1615-1624Article in journal (Refereed)
    Abstract [en]

    Epidermal growth factor (EGF) and estrogen are potent regulators of breast tumorigenesis. Their short-term actions on human breast epithelial cells have been investigated extensively. However, the consequence of a long-term exposure to EGF and estrogen remains to be fully elucidated. The present study examined the effects of long-term exposure to EGF and 17 beta-estradiol on the proliferation, transformation, expression of markers of stemness, and tumorigenesis of MCF7 human breast adenocarcinoma cells. Exposure to EGF and/or 17 beta-estradiol irreversibly enhanced the proliferation rate of MCF7 cells, even following withdrawal. However, in a mouse xenograft experiment, no significant difference in tumor volume was observed between tumors derived from cells exposed to EGF, 17 beta-estradiol or EGF + 17 beta-estradiol. Immunohistochemistry performed on tumors derived from 17 beta-estradiol-exposed cells revealed reduced cell proliferation and vessel scores, according to the results obtained using Ki67 and von Willebrand factor staining, respectively. The EGF-and/or 17 beta-estradiol-treated cells exhibited an increased ratio of cluster of differentiation (CD) 44(+)/CD24(-) cells and enhanced ability to form mammospheres. Furthermore, the long-term exposure of MCF7 cells to EGF and 17 beta-estradiol altered their responsiveness to short-term stimulatory or inhibitory treatments with EGF, 17 beta-estradiol, transforming growth factor-beta 1 (TGF beta 1), Iressa and SB431542. Therefore, the findings indicated that sustained exposure of MCF7 cells to EGF and/or 17 beta-estradiol resulted in enhanced cell proliferation and mammosphere formation, an increased ratio of CD 44(+)/CD24 cells, and altered responses to short-term treatments with EGF, 17 beta-estradiol, TGF beta 1, and drugs inhibiting these signaling pathways. However, this sustained exposure was not sufficient to affect tumor take or volume in a xenograft mouse model.

  • 34.
    Cunha, Sara I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Milan, Italy..
    Lampugnani, Maria Grazia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Inst Mol Oncol, Milan, Italy.;Ist Ric Farmacol Mario Negri, Milan, Italy..
    Deregulated TGF-beta/BMP Signaling in Vascular Malformations2017In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 121, no 8, p. 981-999Article, review/survey (Refereed)
    Abstract [en]

    Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-beta/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-beta/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-beta/BMP receptor complex and the second to increased signaling sensitivity to TGF-beta/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.

  • 35.
    Cuttano, Roberto
    et al.
    IFOM, Milan, Italy..
    Rudini, Noemi
    IFOM, Milan, Italy..
    Bravi, Luca
    IFOM, Milan, Italy..
    Corada, Monica
    IFOM, Milan, Italy..
    Giampietro, Costanza
    IFOM, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy..
    Papa, Eleanna
    IFOM, Milan, Italy..
    Morini, Marco Francesco
    IFOM, Milan, Italy..
    Maddaluno, Luigi
    IFOM, Milan, Italy..
    Baeyens, Nicolas
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Adams, Ralf H.
    Univ Munster, Max Planck Inst Mol Biomed, Fac Med, Dept Tissue Morphogenesis, D-48149 Munster, Germany..
    Jain, Mukesh K.
    Case Cardiovasc Res Inst, Cleveland, OH USA.;Harrington Heart & Vasc Inst, Cleveland, OH USA.;Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH USA.;Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Cleveland, OH USA..
    Owens, Gary K.
    Univ Virginia, Sch Med, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA..
    Schwartz, Martin
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Lampugnani, Maria Grazia
    IFOM, Milan, Italy.;Mario Negri Inst Pharmacol Res, Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. IFOM, Milan, Italy.;Univ Milan, Dept Oncol & Oncohematol, Milan, Italy..
    KLF4 is a key determinant in the development and progression of cerebral cavernous malformations2016In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 8, no 1, p. 6-24Article in journal (Refereed)
    Abstract [en]

    Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFb/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFb/ BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFb/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.

  • 36.
    De La Fuente, Alerie Guzman
    et al.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Lange, Simona
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria..
    Silva, Maria Elena
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile.;Univ Austral Chile, Inst Pharm, Fac Sci, Valdivia, Chile..
    Gonzalez, Ginez A.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Tempfer, Herbert
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Tendon & Bone Regenerat, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    van Wijngaarden, Peter
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Univ Melbourne, Dept Surg, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia,Ophthalmol, Melbourne, Vic, Australia..
    Zhao, Chao
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Di Canio, Ludovica
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Trost, Andrea
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Ophthalmol Optometry & Res Program Expt Ophthalmo, A-5020 Salzburg, Austria..
    Bieler, Lara
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Zaunmair, Pia
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Rotheneichner, Peter
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    O'Sullivan, Anna
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Couillard-Despres, Sebastien
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Errea, Oihana
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Mäe, Maarja A.
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    He, Liqun
    Tianjin Med Univ, Key Lab Post Neuroinjury Neuro Repair & Regenerat, Tianjin Neurol Inst, Dept Neurosurg,Gen Hosp,Minist Educ & Tianjin Cit, Tianjin 300052, Peoples R China..
    Keller, Annika
    Zurich Univ, Zurich Univ Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Batiz, Luis F.
    Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Los Andes, Fac Med, CIB, Santiago, Chile..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Aigner, Ludwig
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    Franklin, Robin J. M.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Rivera, Francisco J.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile..
    Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1755-1764Article in journal (Refereed)
    Abstract [en]

    The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb(ret/ret) mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

  • 37.
    Dejana, Elisabetta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Milan, Italy; niv Milan, Dept Oncol & Hematooncol, Milan, Italy.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Oligodendrocytes follow blood vessel trails in the brain Brain microvasculature is a scaffold for neuroglial migration2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 351, no 6271, p. 341-342Article in journal (Refereed)
  • 38.
    Dejana, Elisabetta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Vasc Biol Unit, I-20129 Milan, Italy..
    Hirschi, Karen K.
    Yale Cardiovasc Res Ctr, Dept Internal Med, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Genet, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Biomed Engn, New Haven, CT 06511 USA..
    Simons, Michael
    Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, Dept Internal Med, 333 Cedar St, New Haven, CT 06511 USA.;Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06511 USA..
    The molecular basis of endothelial cell plasticity2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14361Article, review/survey (Refereed)
    Abstract [en]

    The endothelium is capable of remarkable plasticity. In the embryo, primitive endothelial cells differentiate to acquire arterial, venous or lymphatic fates. Certain endothelial cells also undergo hematopoietic transition giving rise to multi-lineage hematopoietic stem and progenitors while others acquire mesenchymal properties necessary for heart development. In the adult, maintenance of differentiated endothelial state is an active process requiring constant signalling input. The failure to do so leads to the development of endothelial-to-mesenchymal transition that plays an important role in pathogenesis of a number of diseases. A better understanding of these phenotypic changes may lead to development of new therapeutic interventions.

  • 39.
    Dias, Mariana
    et al.
    Theodor Kocher Inst, Bern, Switzerland..
    Coisne, Caroline
    Theodor Kocher Inst, Bern, Switzerland..
    Baden, Pascale
    Theodor Kocher Inst, Bern, Switzerland..
    Lazarevic, Ivana
    Theodor Kocher Inst, Bern, Switzerland..
    Francisco, David
    Univ Bern, Bern, Switzerland..
    Lyck, Ruth
    Theodor Kocher Inst, Bern, Switzerland..
    Enzmann, Gaby
    Theodor Kocher Inst, Bern, Switzerland..
    Deutsch, Urban
    Theodor Kocher Inst, Bern, Switzerland..
    Bruggmann, Remy
    Univ Bern, Bern, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Uppsala, Sweden..
    Furuse, Mikio
    Natl Inst Physiol Sci, Okazaki, Aichi, Japan..
    Engelhardt, Britta
    Theodor Kocher Inst, Bern, Switzerland..
    Claudin 3-Deficient C57BL/6 Mice Display Intact Brain Barriers2017In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 54, p. 63-63Article in journal (Other academic)
  • 40.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Osteoglycin - A switch from angiogenesis to T-cell recruitment?2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 35, p. 22-23Article in journal (Other academic)
  • 41.
    Ding, Bi-Sen
    et al.
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China.;Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Liu, Catherine H.
    Cornell Univ, Dept Pathol & Lab Med, Ctr Vasc Biol, Weill Cornell Med, New York, NY 10021 USA..
    Sun, Yue
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China..
    Chen, Yutian
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China..
    Swendeman, Steven L.
    Cornell Univ, Dept Pathol & Lab Med, Ctr Vasc Biol, Weill Cornell Med, New York, NY 10021 USA.;Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA..
    Jung, Bongnam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Chavez, Deebly
    Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Cao, Zhongwei
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China.;Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Christoffersen, Christina
    Rigshosp, Dept Clin Biochem, Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark..
    Nielsen, Lars Bo
    Rigshosp, Dept Clin Biochem, Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.;Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark..
    Schwab, Susan R.
    NYU, Sch Med, Dept Pathol, Skirball Inst, New York, NY USA..
    Rafii, Shahin
    Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Hla, Timothy
    Cornell Univ, Dept Pathol & Lab Med, Ctr Vasc Biol, Weill Cornell Med, New York, NY 10021 USA.;Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA..
    HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P(1)) promotes regeneration and suppresses fibrosis in the liver2016In: JCI Insight, ISSN 2379-3708, Vol. 1, no 21, article id e87058Article in journal (Refereed)
    Abstract [en]

    Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P 1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this "maladaptive repair" phenotype was recapitulated in mice that lack S1P 1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P 1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P 1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.

  • 42.
    Ebarasi, Lwaki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ashraf, Shazia
    Bierzynska, Agnieszka
    Gee, Heon Yung
    McCarthy, Hugh J.
    Lovric, Svjetlana
    Sadowski, Carolin E.
    Pabst, Werner
    Vega-Warner, Virginia
    Fang, Humphrey
    Koziell, Ania
    Simpson, Michael A.
    Dursun, Ismail
    Serdaroglu, Erkin
    Levy, Shawn
    Saleem, Moin A.
    Hildebrandt, Friedhelm
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome2015In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 1, p. 153-161Article in journal (Refereed)
    Abstract [en]

    Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

  • 43.
    Eleftheriou, Nikolas M.
    et al.
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Sjolund, Jonas
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Bocci, Matteo
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Cortez, Eliane
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Lee, Se-Jin
    Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA..
    Cunha, Sara I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Pietras, Kristian
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-beta signaling2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 51, p. 84314-84325Article in journal (Refereed)
    Abstract [en]

    Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-beta family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown. Furthermore, the knockout of Gdf2 (BMP9), the primary ligand for ALK1 and endoglin, exhibited a mixed phenotype from each of ALK1 and endoglin deficiencies; overall primary tumor burden decreased, but hepatic metastases increased. Tumors lacking BMP9 display a hyperbranching vasculature, and an increase in vascular mesenchymal-marker expression, which may be implicit in the increase in metastases. Taken together, our work cautions against singular blockade of BMP9 and instead demonstrates the utility of dual blockade of ALK1 and endoglin as a strategy for anti-angiogenic therapy in PanNET.

  • 44.
    Erba, Benedetta Gaia
    et al.
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Gruppi, Cristian
    Univ Pavia, Dept Mol Med, Pavia, Italy..
    Corada, Monica
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Pisati, Federica
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy.;Cogentech, Hystopatol Unit, Milan, Italy..
    Rosti, Vittorio
    Policlin San Matteo Fdn, Ctr Study & Treatment Myelofibrosis, Ctr Study Myelofibrosis, Biotechnol Res Labs,Ist Ricovero & Cura Carattere, Pavia, Italy..
    Bartalucci, Niccolo'
    Univ Florence, Sect Haematol, Dept Med & Surg Care, Florence, Italy..
    Villeval, Jean-Luc
    Inst Gustave Roussy, INSERM, U1009, Villejuif, France.;Univ Paris XI, Villejuif, France..
    Vannucchi, Alessandro Maria
    Univ Florence, Sect Haematol, Dept Med & Surg Care, Florence, Italy..
    Barosi, Giovanni
    Policlin San Matteo Fdn, Ctr Study & Treatment Myelofibrosis, Ctr Study Myelofibrosis, Biotechnol Res Labs,Ist Ricovero & Cura Carattere, Pavia, Italy..
    Balduini, Alessandra
    Univ Pavia, Dept Mol Med, Pavia, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Endothelial-to-Mesenchymal Transition in Bone Marrow and Spleen of Primary Myelofibrosis2017In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 8, p. 1879-1892Article in journal (Refereed)
    Abstract [en]

    Primary myelofibrosis is characterized by the development of fibrosis in the bone marrow that contributes to ineffective hematopoiesis. Bone marrow fibrosis is the result of a complex and not yet fully understood interaction among megakaryocytes, myeloid cells, fibroblasts, and endothelial cells. Here, we report that >30% of the endothelial cells in the small vessels of the bone marrow and spleen of patients with primary myelofibrosis have a mesenchymal phenotype, which is suggestive of the process known as endothelial-to-mesenchymal transition (EndMT). EndMT can be reproduced in vitro by incubation of cultured endothelial progenitor cells or spleen-derived endothelial cells with inflammatory cytokines. Megakaryocytes appear to be implicated in this process, because EndMT mainly occurs in the microvessels close to these cells, and because megakaryocyte-derived supernatant fluid can reproduce the EndMT switch in vitro. Furthermore, EndMT is an early event in a JAK2-V617F knock-in mouse model of primary myelofibrosis. Overall, these data show for the first time that microvascular endothelial cells in the bone marrow and spleen of patients with primary myelofibrosis show functional and morphologic changes that are associated to the mesenchymal phenotype.

  • 45.
    Eriksson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Milenova, Ioanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Moreno, Rafael
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alemany, Ramon
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Activating CD40 While Inhibiting IL6R Induces Cytokine Production without PDL1 Upregulation in DCs2017In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 54-54Article in journal (Other academic)
  • 46.
    Eriksson, Emma