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  • 1.
    Aase, Karin
    et al.
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Ernkvist, Mira
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Ebarasi, Lwaki
    Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Jakobsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Majumdar, Arindam
    Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Yi, Chunling
    Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
    Birot, Olivier
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Ming, Yue
    Department of Clinical Neuroscience, Section of Ophthalmology and Vision, Karolinska Institutet, St Erik’s Hospital, SE-11284 Stockholm, Sweden.
    Kvanta, Anders
    Department of Clinical Neuroscience, Section of Ophthalmology and Vision, Karolinska Institutet, St Erik’s Hospital, SE-11284 Stockholm, Sweden.
    Edholm, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Aspenström, Pontus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kissil, Joseph
    Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Shimono, Akihiko
    Vertebrate Body Plan, Center for Developmental Biology, RIKEN Kobe, Chuou-ku, Kobe 650-0047, Japan.
    Holmgren, Lars
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Angiomotin regulates endothelial cell migration during embryonic angiogenesis2007In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, no 16, p. 2055-2068Article in journal (Refereed)
    Abstract [en]

    The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.

  • 2.
    Bahram, Fuad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    VEGF-mediated signal transduction in lymphatic endothelial cells2010In: Pathophysiology : the official journal of the International Society for Pathophysiology / ISP, ISSN 0928-4680, Vol. 17, no 4, p. 253-261Article in journal (Refereed)
    Abstract [en]

    The VEGF family of angiogenic ligands consists of VEGFA, VEGFB, VEGFC, VEGFD and placenta growth factor, PlGF. These growth factors bind in an overlapping pattern to three receptor tyrosine kinases, denoted VEGFR1, VEGFR2 and VEGFR3. Originally, VEGFA (the prototype VEGF) was described as a master regulator of vascular endothelial cell biology in vitro and in vivo, transducing its effect through VEGFR2. VEGFA, VEGFB and PlGF bind to VEGFR1, which is a negative regulator of endothelial cell function at least during embryogenesis. VEGFC and VEGFD were identified as lymphatic endothelial factors, acting via VEGFR3. With time, the very clear distinction between the roles of the VEGF ligands in angiogenesis/lymphangiogenesis has given way for a more complex pattern. It seems that the biology of the different VEGFR2 and VEGFR3 ligands overlaps quite extensively and that both receptor types contribute to angiogenesis as well as lymphangiogenesis. This paradigm shift in our understanding is due to the access to more sophisticated reagents and techniques revealing dynamic and plastic expression of ligands and receptors in different physiological and pathological conditions. Moreover, knowledge on the important role of VEGF coreceptors, the neuropilins, in regulating the responsiveness to VEGF has changed our perception on the mechanism of VEGF signal transduction. This review will primarily focus on the properties of VEGR3, its signal transduction and the resulting biology.

  • 3. Bentley, Katie
    et al.
    Franco, Claudio Areias
    Philippides, Andrew
    Blanco, Raquel
    Dierkes, Martina
    Gebala, Veronique
    Stanchi, Fabio
    Jones, Martin
    Aspalter, Irene M.
    Cagna, Guiseppe
    Weström, Simone
    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, Cancer and Vascular Biology.
    Vestweber, Dietmar
    Gerhardt, Holger
    The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis2014In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 16, no 4, p. 309-321Article in journal (Refereed)
    Abstract [en]

    Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.

  • 4. Berge, Tone
    et al.
    Sundvold-Gjerstad, Vibeke
    Granum, Stine
    Andersen, Thorny C.
    Holthe, Gunn B.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andreotti, Amy H.
    Inngjerdingen, Marit
    Spurkland, Anne
    T cell specific adapter protein (TSAd) interacts with Tec kinase ITK to promote CXCL12 induced migration of human and murine T cells2010In: PloS one, ISSN 1932-6203, Vol. 5, no 3, p. e9761-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The chemokine CXCL12/SDF-1alpha interacts with its G-protein coupled receptor CXCR4 to induce migration of lymphoid and endothelial cells. T cell specific adapter protein (TSAd) has been found to promote migration of Jurkat T cells through interaction with the G protein beta subunit. However, the molecular mechanisms for how TSAd influences cellular migration have not been characterized in detail. PRINCIPAL FINDINGS: We show that TSAd is required for tyrosine phosphorylation of the Lck substrate IL2-inducible T cell kinase (Itk). Presence of Itk Y511 was necessary to boost TSAd's effect on CXCL12 induced migration of Jurkat T cells. In addition, TSAd's ability to promote CXCL12-induced actin polymerization and migration of Jurkat T lymphocytes was dependent on the Itk-interaction site in the proline-rich region of TSAd. Furthermore, TSAd-deficient murine thymocytes failed to respond to CXCL12 with increased Itk phosphorylation, and displayed reduced actin polymerization and cell migration responses. CONCLUSION: We propose that TSAd, through its interaction with both Itk and Lck, primes Itk for Lck mediated phosphorylation and thereby regulates CXCL12 induced T cell migration and actin cytoskeleton rearrangements.

  • 5. Bhattacharya, Resham
    et al.
    Kwon, Junhye
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wang, Enfeng
    Patra, Sujata
    Bida, John Paul
    Bajzer, Zeljko
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mukhopadhyay, Debabrata
    Distinct role of PLC{beta}3 in VEGF-mediated directional migration and vascular sprouting2009In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 122, no 7, p. 1025-1034Article in journal (Refereed)
    Abstract [en]

    Endothelial cell proliferation and migration is essential to angiogenesis. Typically, proliferation and chemotaxis of endothelial cells is driven by growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF activates phospholipases (PLCs) - specifically PLCgamma1 - that are important for tubulogenesis, differentiation and DNA synthesis. However, we show here that VEGF, specifically through VEGFR2, induces phosphorylation of two serine residues on PLCbeta3, and this was confirmed in an ex vivo embryoid body model. Knockdown of PLCbeta3 in HUVEC cells affects IP3 production, actin reorganization, migration and proliferation; whereas migration is inhibited, proliferation is enhanced. Our data suggest that enhanced proliferation is precipitated by an accelerated cell cycle, and decreased migration by an inability to activate CDC42. Given that PLCbeta3 is typically known as an effector of heterotrimeric G-proteins, our data demonstrate a unique crosstalk between the G-protein and receptor tyrosine kinase (RTK) axes and reveal a novel molecular mechanism of VEGF signaling and, thus, angiogenesis.

  • 6.
    Blume-Jensen, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Zsebo, Krisztina M.
    AMGEN Inc., AMGEN Center, Thousand Oaks, CA 91320, USA.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis1991In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 10, no 13, p. 4121-4128Article in journal (Refereed)
    Abstract [en]

    The proto-oncogene c-kit is allelic with the murine white spotting (W) locus and encodes a transmembrane protein tyrosine kinase that is structurally related to the receptors for platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1). Recently the ligand for the c-kit product, stem cell factor (SCF), was identified in both transmembrane and soluble forms. In order to examine the mechanism for receptor activation by SCF and biological properties of the activated c-kit product, we transfected the wild-type human c-kit cDNA into porcine aortic endothelial cells. We found that the receptor was down-regulated and transmitted a mitogenic signal in response to stimulation with soluble SCF. We also demonstrate that SCF induces dimerization of the c-kit product in intact cells, and that dimerization of the receptor is correlated with activation of its kinase. Activation of the c-kit product by SCF was found to induce circular actin reorganization indistinguishable from that mediated by the PDGF beta-receptor in response to PDGF-BB. Furthermore, soluble SCF was a potent chemotactic agent for cells expressing the c-kit product, a property which might be of importance during embryonic development.

  • 7.
    Bohman, Svante
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Matsumoto, Taro
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Suh, Kwang
    Dimberg, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Jakobsson, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Yuspa, Stuart
    Claesson-Welsh, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Proteomic analysis of vascular endothelial growth factor-induced endothelial cell differentiation reveals a role for chloride intracellular channel 4 (CLIC4) in tubular morphogenesis.2005In: J Biol Chem, ISSN 0021-9258, Vol. 280, no 51, p. 42397-404Article in journal (Refereed)
  • 8.
    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)
  • 9.
    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.

  • 10.
    Christofferson, R
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Claesson-Welsh, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Muhr, C
    Angiogeneshämmare sannolikt komplement vid cancerbehandlingar2002In: Läkartidningen, Vol. 99, p. 4138-Article in journal (Other academic)
  • 11.
    Claesson-Welsh, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    [Islet of Langerhans transplantation in type I diabetes. Regulation of neovascularization in the transplant is a key question]2003In: Lakartidningen, Vol. 100, p. 1210-Article in journal (Other academic)
  • 12.
    Claesson-Welsh, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Signal transduction by vascular endothelial growth factor receptors.2003In: Biochem Soc Trans, Vol. 31, p. 20-Article in journal (Refereed)
  • 13.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    ADAM-mediated shedding, a new flavor in angiogenesis regulation2010In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 30, no 11, p. 2087-2088Article in journal (Other academic)
  • 14.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Blood vessels as targets in tumor therapy2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 178-186Article, review/survey (Refereed)
    Abstract [en]

    The landmark papers published by Judah Folkman in the early 1970s on tumor angiogenesis and therapeutic implications promoted the rapid development of a very dynamic field where basic scientists, oncologists, and pharmaceutical industry joined forces to determine the molecular mechanisms in blood vessel formation and find means to exploit this knowledge in suppressing tumor vascularization and growth. A wealth of information has been collected on angiogenic growth factors, and in 2004 the first specific blood vessel-targeted cancer therapy was introduced: a neutralizing antibody against vascular endothelial growth factor (VEGF). Now (2011) we know that suppression of tumor angiogenesis may be a double-edged sword and that the therapy needs to be further refined and individualized. This review describes the hallmarks of tumor vessels, how different angiogenic growth factors exert their function, and the perspectives for future development of anti-angiogenic therapy.

  • 15.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Healing hemangiomas2008In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 14, no 11, p. 1147-8Article in journal (Other academic)
  • 16.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Introduction to symposium on vascular biology, metabolism and cancer2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 2, p. 112-113Article in journal (Refereed)
  • 17.
    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)
  • 18.
    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)
  • 19.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Receptor Talk and Tumor Cell Walk in Glioblastoma2012In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 22, no 1, p. 1-2Article in journal (Other academic)
    Abstract [en]

    In this issue of Cancer Cell, Lu et al. describe unconventional molecular interactions in glioblastoma cells that provide a mechanism for how anti-vascular endothelial growth factor therapy may promote mesenchymal transition of glioblastoma cells and increase tumor invasion.

  • 20.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Signal transduction by vascular endothelial growth factor receptors2012In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 56, no 5-6, p. 308-308Article in journal (Other academic)
  • 21.
    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.

  • 22.
    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.

  • 23.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    VEGF-B taken to our hearts: specific effect of VEGF-B in myocardial ischemia2008In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, no 9, p. 1575-6Article in journal (Other academic)
  • 24.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gerhardt, Holger
    Introduction to the ECR special angiogenesis issue2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 9, p. 1239-1239Article in journal (Other academic)
  • 25.
    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)
  • 26.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    VEGFA and tumour angiogenesis2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 2, p. 114-127Article, review/survey (Refereed)
    Abstract [en]

    In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.

  • 27.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ito, Nobuyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anand-Apte, Bela
    Soker, Shay
    Setter, Bruce
    O´Reilly, Michael
    Folkman, Judah
    Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 10, p. 5579-5583Article in journal (Refereed)
    Abstract [en]

    Angiostatin, a fragment of plasminogen, has been identified and characterized as an endogenous inhibitor of neovascularization. We show that angiostatin treatment of endothelial cells in the absence of growth factors results in an increased apoptotic index whereas the proliferation index is unchanged. Angiostatin also inhibits migration and tube formation of endothelial cells. Angiostatin treatment has no effect on growth factor-induced signal transduction but leads to an RGD-independent induction of the kinase activity of focal adhesion kinase, suggesting that the biological effects of angiostatin relate to subversion of adhesion plaque formation in endothelial cells.

  • 28.
    Cross, Michael J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lu, Lingge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nyqvist, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Holmqvist, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulatesthe Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, no 8, p. 2881-2893Article in journal (Refereed)
    Abstract [en]

    Stimulation of fibroblast growth factor receptor-1 (FGFR-1) is known to result in phosphorylation of tyrosine 766 and the recruitment and subsequent activation of phospholipase C-γ (PLC-γ). To assess the role of tyrosine 766 in endothelial cell function, we generated endothelial cells expressing a chimeric receptor, composed of the extracellular domain of the PDGF receptor-α and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC-γ activation and resulted in a reduced phosphorylation of FRS2 and reduced activation of the Ras/MEK/MAPK pathway relative to the wild-type chimeric receptor. However, FGFR-1–mediated MAPK activation was not dependent on PKC activation or intracellular calcium, both downstream mediators of PLC-γ activation. We report that the adaptor protein Shb is also able to bind tyrosine 766 in the FGFR-1, via its SH2 domain, resulting in its subsequent phosphorylation. Overexpression of an SH2 domain mutant Shb caused a dramatic reduction in FGFR-1–mediated FRS2 phosphorylation with concomitant perturbment of the Ras/MEK/MAPK pathway. Expression of the chimeric receptor mutant and the Shb SH2 domain mutant resulted in a similar reduction in FGFR-1–mediated mitogenicity. We conclude, that Shb binds to tyrosine 766 in the FGFR-1 and regulates FGF-mediated mitogenicity via FRS2 phosphorylation and the subsequent activation of the Ras/MEK/MAPK pathway.

  • 29. Cross, MJ
    et al.
    Dixelius, J
    Matsumoto, T
    Claesson-Welsh, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    VEGF-receptor signal transduction2003In: Trends Biochem Sci, Vol. 28, p. 488-Article in journal (Refereed)
  • 30. Cébe-Suarez, Stéphanie
    et al.
    Grünewald, Felix S.
    Jaussi, Rolf
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mercer, Andrew A.
    Prota, Andrea E.
    Ballmer-Hofer, Kurt
    Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR2008In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 22, no 8, p. 3078-3086Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factors (VEGFs) interact with the receptor tyrosine kinases (RTKs) VEGFR-1, -2, and -3; neuropilins (NRPs); and heparan sulfate (HS) proteoglycans. VEGF RTKs signal to downstream targets upon ligand-induced tyrosine phosphorylation, while NRPs and HS act as coreceptors that lack enzymatic activity yet modulate signal output by VEGF RTKs. VEGFs exist in various isoforms with distinct receptor specificity and biological activity. Here, a series of mammalian VEGF-A splice variants and orf virus VEGF-Es, as well as chimeric and mutant VEGF variants, were characterized to determine the motifs required for binding to NRP-1 in the absence (VEGF-E) or presence (VEGF-A(165)) of an HS-binding sequence. We identified the carboxyterminal peptides RPPR and DKPRR as the NRP-1 binding motifs of VEGF-E and VEGF-A, respectively. RPPR had significantly higher affinity for NRP-1 than DKPRR. VEGFs containing an RPPR motif promoted HS-independent coreceptor complex assembly between VEGFR-2 and NRP-1, independent of whether these receptors were expressed on the same or separate cells grown in cocultures. Functional studies showed that stable coreceptor assembly by VEGF correlated with its ability to promote vessel formation in an embryoid body angiogenesis assay.

  • 31.
    Dimberg, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rylova, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dieterich, Lothar C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Schiller, Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wikner, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bohman, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wawrousek, Eric F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis2008In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, no 4, p. 2015-2023Article in journal (Refereed)
    Abstract [en]

    Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alpha B-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alpha B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alpha B-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alpha B-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alpha B-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alpha B-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of anglogenic modulators.

  • 32. Dixelius, J
    et al.
    Cross, MJ
    Matsumoto, T
    Claesson-Welsh, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Endostatin action and intracellular signaling: beta-catenin as a potential target?2003In: Cancer Lett, Vol. 196, p. 1-Article in journal (Refereed)
  • 33.
    Dixelius, J
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Jakobsson, L
    Genersch, E
    Bohman, S
    Ekblom, P
    Claesson-Welsh, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Angiogenesis in Synergy with Fibroblast Growth Factor by Distinct Regulation of the Gene and Protein. Expression Profile in Endothelial Cells.2004In: J Biol Chem, Vol. 279, p. 23766-Article in journal (Refereed)
  • 34.
    Dixelius, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Larsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Sasaki, Takako
    Holmqvist, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lu, Lingge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Timpl, Rupert
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Cancer and Vascular Biology.
    Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis2000In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 95, no 11, p. 3403-3411Article in journal (Refereed)
    Abstract [en]

    Endostatin, which corresponds to the C-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis. Fibroblast growth factor-2 (FGF-2)-induced angiogenesis in the chicken chorioallantoic membrane was inhibited by endostatin, but not by an endostatin mutant R158/270A, lacking heparin-binding ability. Endostatin was internalized by endothelial cells, but not by mouse fibroblasts. Treatment of murine brain endothelial (IBE) cells with endostatin reduced the proportion of cells in S phase, whereas growth-arrested IBE cells in collagen gels treated with endostatin displayed enhanced tubular morphogenesis. IBE cells overexpressing Shb, an adaptor protein implicated in angiostatin-induced apoptosis, displayed elevated apoptosis and decreased tubular morphogenesis in collagen gels in response to endostatin when added together with FGF-2. Induction of apoptosis was dependent on the heparin-binding ability of endostatin and the expression of Shb with a functional Src homology 2 (SH2)-domain. Endostatin treatment for 10 minutes or 24 hours induced tyrosine phosphorylation of Shb and formation of multiprotein complexes. An Shb SH2 domain fusion protein precipitated a 125-kd phosphotyrosyl protein in endostatin-treated cells. The 125-kd component either contained intrinsic tyrosine kinase activity or occurred in complex with a tyrosine kinase. In conclusion, our data show that endostatin induces tyrosine kinase activity and enhanced apoptosis in FGF-treated endothelial cells.

  • 35.
    Dixelius, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mäkinen, Taija
    Wirzenius, Maria
    Karkkainen, Marika J.
    Wernstedt, Christer
    Ludwiginstitutet för Cancerforskning.
    Alitalo, Kari
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites2003In: J Biol Chem, Vol. 278, p. 40973-Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factors (VEGFs) regulate the development and growth of the blood and lymphatic vascular systems. Of the three VEGF receptors (VEGFR), VEGFR-1 and -2 are expressed on blood vessels; VEGFR-2 is found also on lymphatic vessels. VEGFR-3 is expressed mainly on lymphatic vessels but it is also up-regulated in tumor angiogenesis. Although VEGFR-3 is essential for proper lymphatic development, its signal transduction mechanisms are still incompletely understood. Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the VEGFR-3 carboxyl-terminal tail. These sites were used both in VEGFR-3 overexpressed in 293 cells and when the endogenous VEGFR-3 was activated in lymphatic endothelial cells. Interestingly, VEGF-C stimulation of lymphatic endothelial cells also induced the formation of VEGFR-3/VEGFR-2 heterodimers, in which VEGFR-3 was phosphorylated only at three of the five sites while the two most carboxyl-terminal tyrosine residues appeared not to be accessible for the VEGFR-2 kinase. Our data suggest that the carboxyl-terminal tail of VEGFR-3 provides important regulatory tyrosine phosphorylation sites with potential signal transduction capacity and that these sites are differentially used in ligand-induced homo- and heterodimeric

  • 36.
    Dixelius, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lee, Chunsik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 4, p. 2089-97Article in journal (Refereed)
    Abstract [en]

    Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline-rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/proline-rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate alpha-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving alpha(v)beta3 integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility.

  • 37. Eriksson , K
    et al.
    Magnusson, P
    Dixelius, J
    Claesson-Welsh, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Cross, MJ
    Angiostatin and endostatin inhibit endothelial cell migration in response to FGF and VEGF without interfering with specific intracellular signal transduction pathways.2003In: FEBS Lett. , Vol. 536, p. 19-Article in journal (Refereed)
  • 38.
    Fernandez-Alonso, R.
    et al.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Martin-Lopez, M.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Gonzalez-Cano, L.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Garcia, S.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Castrillo, F.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Diez-Prieto, I.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Univ Leon, Dept Med Cirugia & Anat Vet, E-24071 Leon, Spain..
    Fernandez-Corona, A.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Complejo Hosp Leon, Leon 24071, Spain..
    Lorenzo-Marcos, M. E.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Complejo Hosp Leon, Leon 24071, Spain..
    Li, Xiujuan
    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, 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 Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75185 Uppsala, Sweden.;Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Marques, M.
    Univ Leon, Inst Desarrollo Ganadero, E-24071 Leon, Spain..
    Marin, M. C.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGF beta signaling2015In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 22, no 8, p. 1287-+Article in journal (Refereed)
    Abstract [en]

    Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-beta and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

  • 39.
    Fleetwood, Filippa
    et al.
    AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Div Prot Technol,KTH, S-10691 Stockholm, Sweden..
    Guler, Rezan
    AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Div Prot Technol,KTH, S-10691 Stockholm, Sweden..
    Gordon, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stahl, Stefan
    AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Div Prot Technol,KTH, S-10691 Stockholm, Sweden..
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lofblom, John
    AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Div Prot Technol,KTH, S-10691 Stockholm, Sweden..
    Novel affinity binders for neutralization of vascular endothelial growth factor (VEGF) signaling2016In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 73, no 8, p. 1671-1683Article in journal (Refereed)
    Abstract [en]

    Angiogenesis denotes the formation of new blood vessels from pre-existing vasculature. Progression of diseases such as cancer and several ophthalmological disorders may be promoted by excess angiogenesis. Novel therapeutics to inhibit angiogenesis and diagnostic tools for monitoring angiogenesis during therapy, hold great potential for improving treatment of such diseases. We have previously generated so-called biparatopic Affibody constructs with high affinity for the vascular endothelial growth factor receptor-2 (VEGFR2), which recognize two non-overlapping epitopes in the ligand-binding site on the receptor. Affibody molecules have previously been demonstrated suitable for imaging purposes. Their small size also makes them attractive for applications where an alternative route of administration is beneficial, such as topical delivery using eye drops. In this study, we show that decreasing linker length between the two Affibody domains resulted in even slower dissociation from the receptor. The new variants of the biparatopic Affibody bound to VEGFR2-expressing cells, blocked VEGFA binding, and inhibited VEGFA-induced signaling of VEGFR2 over expressing cells. Moreover, the biparatopic Affibody inhibited sprout formation of endothelial cells in an in vitro angiogenesis assay with similar potency as the bivalent monoclonal antibody ramucirumab. This study demonstrates that the biparatopic Affibody constructs show promise for future therapeutic as well as in vivo imaging applications.

  • 40. Geretti, Elena
    et al.
    van Meeteren, Laurens A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Shimizu, Akio
    Dudley, Andrew C.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klagsbrun, Michael
    A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression2010In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 8, no 8, p. 1063-1073Article in journal (Refereed)
    Abstract [en]

    Neuropilins (NRP1 and NRP2) are coreceptors for vascular endothelial growth factor (VEGF) and mediate angiogenesis and tumor progression. VEGF binds to the NRP1 and NRP2 B domains. Previously, it was shown that mutagenesis of the soluble NRP2 B domain (MutB-NRP2) increased affinity to VEGF by 8-fold. Here, we show that MutB-NRP2 inhibited (125)I-VEGF binding to NRP1, NRP2, and VEGFR-2. It antagonized VEGF-induced VEGFR-2/NRP2 complex formation and inhibited VEGF-induced activation of AKT, a mediator of cell survival, without affecting activation of VEGFR-2. In three-dimensional embryoid bodies, a model of VEGF-induced angiogenesis, MutB-NRP2 inhibited VEGF-induced sprouting. When overexpressed in human melanoma cells, MutB-NRP2 inhibited tumor growth compared with control tumors. Avastin (bevacizumab), a monoclonal antibody to VEGF, inhibited VEGF interactions with VEGFR-2, but not with NRPs. The combination of MutB-NRP2 and Avastin resulted in an enhanced inhibition of human melanoma tumor growth compared with MutB-NRP2 treatment only or Avastin treatment only. In conclusion, these results indicate that MutB-NRP2 is a novel antagonist of VEGF bioactivity and tumor progression.

  • 41.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Beskow, Anna H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Henriksson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 42. Hagberg, Carolina E.
    et al.
    Falkevall, Annelie
    Wang, Xun
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Huusko, Jenni
    Nilsson, Ingrid
    van Meeteren, Laurens A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Samen, Erik
    Lu, Li
    Vanwildemeersch, Maarten
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genove, Guillem
    Pietras, Kristian
    Stone-Elander, Sharon
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ylä-Herttuala, Seppo
    Lindahl, Per
    Eriksson, Ulf
    Vascular endothelial growth factor B controls endothelial fatty acid uptake2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 464, no 7290, p. 917-921Article in journal (Refereed)
    Abstract [en]

    The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.

  • 43.
    Hansen, Klaus
    et al.
    Ludwiginstitutet för Cancerforskning.
    Rönnstrand, Lars
    Ludwiginstitutet för Cancerforskning.
    Claesson-Welsh, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Carl-Henrik
    Ludwiginstitutet för Cancerforskning.
    Phosphorylation of a 72-kDa protein in PDGF-stimulated cells which forms complex with c-Crk, c-Fyn and Eps15.1997In: FEBS Letters, Vol. 409, p. 195-Article in journal (Refereed)
  • 44.
    Hayashi, Makoto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Adler, Jeremy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sun, Zuyue
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vertuani, Simona
    Hellberg, Carina
    Mellberg, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Koch, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Koh, Gou Young
    Dejana, Elisabetta
    Belting, Heinz-Georg
    Affolter, Markus
    Thurston, Gavin
    Holmgren, Lars
    Vestweber, Dietmar
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    VE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1672-Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) guides the path of new vessel sprouts by inducing VEGF receptor-2 activity in the sprout tip. In the stalk cells of the sprout, VEGF receptor-2 activity is downregulated. Here, we show that VEGF receptor-2 in stalk cells is dephosphorylated by the endothelium-specific vascular endothelial-phosphotyrosine phosphatase (VE-PTP). VE-PTP acts on VEGF receptor-2 located in endothelial junctions indirectly, via the Angiopoietin-1 receptor Tie2. VE-PTP inactivation in mouse embryoid bodies leads to excess VEGF receptor-2 activity in stalk cells, increased tyrosine phosphorylation of VE-cadherin and loss of cell polarity and lumen formation. Vessels in ve-ptp(-/-) teratomas also show increased VEGF receptor-2 activity and loss of endothelial polarization. Moreover, the zebrafish VE-PTP orthologue ptp-rb is essential for polarization and lumen formation in intersomitic vessels. We conclude that the role of Tie2 in maintenance of vascular quiescence involves VE-PTP-dependent dephosphorylation of VEGF receptor-2, and that VEGF receptor-2 activity regulates VE-cadherin tyrosine phosphorylation, endothelial cell polarity and lumen formation.

  • 45.
    Heldin, Carl-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Westermark, Bengt
    Platelet-derived growth factor: isoform-specific signalling via heterodimeric or homodimeric receptor complexes1992In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 41, no 3, p. 571-574Article in journal (Other academic)
    Abstract [en]

    Growth factors are polypeptides that are involved in the regulation of cell growth and differentiation, such as, during the embryonal development, in wound healing, in hematopoiesis, in the immune response, as well as in several adverse reactions including malignancies. Several families of structurally-related growth factors are known; new members of these families continue to be discovered and occasionally new families are found. One of the best characterized growth factor family is the platelet-derived growth factor (PDGF) family. PDGF was originally found to be present in the alpha-granules of platelets and to have growth promoting activity for fibroblasts and smooth muscle cells; subsequent studies have shown that PDGF is synthesized by a large number of different normal as well as transformed cell types, and that it acts not only on connective tissue cells but also on other types of cells [reviewed in 1, 2].

    The present review summarizes some recent developments in the elucidation of the structural and functional properties of PDGF and PDGF receptors, the mechanism for PDGF signalling at the cellular level and the possible in vivo effects of PDGF.

  • 46.
    Heuchel, Rainer
    et al.
    Ludwiginstitutet för Cancerforskning.
    Berg, Ansgar
    Tallquist, Michelle
    Åhlén, Karina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Reed, Rolf K
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Claesson-Welsh, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Carl-Henrik
    Ludwiginstitutet för Cancerforskning.
    Soriano, Philippe
    Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3' kinase signaling1999In: Proc Natl Acad Sci U S A, Vol. 96, no 20, p. 11410-5Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) isoforms lead to mitogenic, survival, and chemotactic responses in a variety of mesenchymal cell types during development and in the adult. We have studied the importance of phosphatidylinositol-3' kinase (PI3K) signaling in these responses by mutating the PI3K-binding sites in the PDGF-beta receptor by gene targeting in embryonic stem cells. Homozygous mutant mice developed normally; however, cells derived from the mutants were less chemotactic and had largely lost their ability to contract collagen gels in response to PDGF. Injection of a mast cell degranulating agent in mice led to a decrease in interstitial fluid pressure resulting in edema formation. In contrast to wild-type mice, mutant mice were unable to normalize the pressure after treatment with PDGF. Taken together, these observations suggest a function for PDGF signaling through PI3K in interstitial fluid homeostasis by modulating the tension between cells and extracellular matrix structures.

  • 47.
    Holmqvist, Kristina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Cross, Michael J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Rolny, Charlotte
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Hägerkvist, Robert
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Rahimi, Nader
    Matsumoto, Taro
    Claesson-Welsh, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Welsh, Michael
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    The adaptor protein Shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration.2004In: J Biological chemistry, Vol. 279, no 21, p. 22267-22275Article in journal (Refereed)
  • 48.
    Honkura, Naoki
    et al.
    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.
    Richards, Mark
    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.
    Laviña, Bàrbara
    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.
    Sainz-Jaspeado, Miguel
    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.
    Betsholtz, Christer
    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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Intravital imaging-based analysis tools for vessel identification and assessment of concurrent dynamic vascular events2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2746Article in journal (Refereed)
    Abstract [en]

    The vasculature undergoes changes in diameter, permeability and blood flow in response to specific stimuli. The dynamics and interdependence of these responses in different vessels are largely unknown. Here we report a non-invasive technique to study dynamic events in different vessel categories by multi-photon microscopy and an image analysis tool, RVDM (relative velocity, direction, and morphology) allowing the identification of vessel categories by their red blood cell (RBC) parameters. Moreover, Claudin5 promoter-driven green fluorescent protein (GFP) expression is used to distinguish capillary subtypes. Intradermal injection of vascular endothelial growth factor A (VEGFA) is shown to induce leakage of circulating dextran, with vessel-type-dependent kinetics, from capillaries and venules devoid of GFP expression. VEGFA-induced leakage in capillaries coincides with vessel dilation and reduced flow velocity. Thus, intravital imaging of non-invasive stimulation combined with RVDM analysis allows for recording and quantification of very rapid events in the vasculature.

  • 49.
    Hooshmand-Rad, Roya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lu, Lingge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Platelet-Derived Growth Factor-Mediated Signaling through the Shb Adaptor Protein: Effects on Cytoskeletal Organization2000In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 257, no 2, p. 245-254Article in journal (Refereed)
    Abstract [en]

    The Src homology (SH) 2 domain adaptor protein Shb has previously been shown to interact with the platelet-derived growth factor (PDGF)-β receptor. In this study we show an association between Shb and the PDGF-α receptor which is mediated by the SH2 domain of Shb and involves tyrosine residue 720 in the kinase insert domain of the receptor. To assess the role of Shb in PDGF-mediated signaling, we have overexpressed wild-type Shb or Shb carrying a mutation (R522K) which renders the SH2 domain inactive, in Patch mouse (PhB) fibroblasts expressing both PDGF receptors (PhB/Rα). Overexpression of wild-type Shb, but not the R522K Shb mutant, affected PDGF-mediated reorganization of the cytoskeleton by decreasing membrane ruffle formation and stimulating the generation of filopodia relative the parental control cells. In addition, the PDGF-induced receptor-associated phosphatidylinositol 3′-kinase activity and phosphorylation of Akt was similar in both PhB/Rα/Shb and PhB/Rα/ShbR522K cells compared with the parental control, whereas the activation of Rac in response to PDGF-BB was diminished only in the PhB/Rα/Shb cells. We conclude that Shb plays a role in PDGF-dependent regulation of certain cytoskeletal changes by modulating the ability of PDGF to activate Rac.

  • 50. Jakobsson, Lars
    et al.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Vascular basement membrane components in angiogenesis: an act of balance2008In: Scientific World Journal, ISSN 1537-744X, E-ISSN 1537-744X, Vol. 8, p. 1246-1249Article in journal (Refereed)
    Abstract [en]

    Angiogenesis is crucial in the progression of a number of pathological conditions, such as diabetic retinopathy, rheumatoid arthritis, psoriasis, and cancer. In contrast to vessels in healthy tissues, the vasculature in these pathologies is highly unstable, constantly dissolving and renewing. Characteristically, vessels in pathologies have discontinuous basement membrane (BM) coverage. The consequences of shifts in BM density and composition are still relatively unknown. Several studies have illustrated that partial loss of the vascular BM during development results in the widening of vessels. This has been suggested to be a result of reduced mechanical resistance to the force inflicted by the blood pressure. However, recent data indicate that depletion of BM laminins (LMs) leads to enlarged vessels even in the absence of cardiac activity and blood pressure. A key question is whether single BM components or fragments thereof play distinct roles in the angiogenic process, or if it is the balance between the different components of the BM that guides the morphology of the new vessel.

123 1 - 50 of 107
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