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  • 1.
    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.

  • 2. 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, Cancer and Vascular Biology.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    The Schlemm's canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 3975-3986Article in journal (Refereed)
    Abstract [en]

    In glaucoma, aqueous outflow into the Schlemm's canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular, system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.

  • 3. 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)
  • 4. 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.

  • 5.
    Frye, Maike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Taddei, Andrea
    Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    Dierkes, Cathrin
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fielden, Matthew
    Albanova Univ Ctr, KTH Royal Inst Technol, Dept Appl Phys, S-10691 Stockholm, Sweden..
    Ortsäter, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kazenwadel, Jan
    Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia.;SA Pathol, Adelaide, SA 5000, Australia..
    Calado, Dinis P.
    Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    Ostergaard, Pia
    St Georges Univ London, Mol & Clin Sci Inst, Lymphovasc Res Unit, London SW17 0RE, England..
    Salminen, Marjo
    Univ Helsinki, Dept Vet Biosci, Helsinki 00014, Finland..
    He, Liqun
    Tianjin Med Univ, Gen Hosp, Minist Educ & Tianjin City, Tianjin Neurol Inst,Dept Neurosurg,Key Lab Post, Tianjin 300052, Peoples R China..
    Harvey, Natasha L.
    Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia.;SA Pathol, Adelaide, SA 5000, Australia..
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany.;Univ Munster, EIMI, D-48149 Munster, Germany..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1511Article in journal (Refereed)
    Abstract [en]

    Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.

  • 6. Lutter, Sophie
    et al.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Regulation of Lymphatic Vasculature by Extracellular Matrix2014In: Developmental Aspects of the Lymphatic Vascular System, Springer Berlin/Heidelberg, 2014, p. 55-65Chapter in book (Refereed)
    Abstract [en]

    The extracellular matrix (ECM) is a complex but highly organized network of macromolecules with different physical, biochemical, and mechanical properties. In addition to providing structural support to tissues, it regulates a variety of cellular responses during development and tissue homeostasis. Interactions between the lymphatic vessels and their ECM are starting to be recognized as important modulators of lymphangiogenesis. Here, we review the current knowledge of the structure and composition of the ECM of lymphatic vessels and discuss the role of individual matrix components and their cell surface receptors in regulating lymphatic vascular development and function.

  • 7.
    Lyons, O. T. A.
    et al.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Saha, P.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Seet, C.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Kuchta, A.
    Guys & St Thomas NHS Fdn Trust, Dept Ultrason Angiol, London, England..
    Arnold, A.
    Guys & St Thomas NHS Fdn Trust, Dept Ultrason Angiol, London, England..
    Grover, S.
    Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA USA..
    Rashbrook, V.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Sabine, A.
    CHU Vaudois, Dept Fundamental Oncol, Epalinges, Switzerland.;Univ Lausanne, Epalinges, Switzerland..
    Vizcay-Barrena, G.
    Kings Coll London, Ctr Ultrastructural Imaging, London, England..
    Patel, A.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Ludwinski, F.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Padayachee, S.
    Guys & St Thomas NHS Fdn Trust, Dept Ultrason Angiol, London, England..
    Kume, T.
    Northwestern Univ, Feinberg Cardiovascular Res Inst, Sch Med, Evanston, IL 60208 USA..
    Kwak, B.
    Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland..
    Brice, G.
    St George Hosp, SW Thames Reg Genet Serv, London, England..
    Mansour, S.
    St George Hosp, SW Thames Reg Genet Serv, London, England..
    Ostergaard, P.
    St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England..
    Mortimer, P.
    St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England..
    Jeffery, S.
    St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England..
    Brown, N.
    St Georges Univ London, Inst Med & Biomed Educ, London, England..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Petrova, T.
    CHU Vaudois, Dept Fundamental Oncol, Epalinges, Switzerland.;Univ Lausanne, Epalinges, Switzerland..
    Modarai, B.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Smith, A.
    Kings Coll London, St Thomas Hosp, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Mechanisms underlying human venous valve disease caused by mutations in Foxc2 and connexin472017In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 104, no Suppl. 3, p. 8-8, article id 5Article in journal (Other academic)
  • 8.
    Lyons, Oliver
    et al.
    Kings Coll London, London, England..
    Saha, Prakash
    St Thomas Hosp, Kings Coll London, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Seet, Christopher
    St Thomas Hosp, Kings Coll London, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Kuchta, Adam
    Guys & St Thomas Fdn Trust, Dept Ultrason Angiol, London, England..
    Arnold, Andrew
    Guys & St Thomas Fdn Trust, Dept Ultrason Angiol, London, England..
    Grover, Steven
    Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, Boston, MA 02215 USA.;Harvard Med Sch, Boston, MA USA..
    Rashbrook, Victoria
    St Thomas Hosp, Kings Coll London, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Sabine, Amelie
    CHU Vaudois, Dept Fundamental Oncol, Epalinges, Switzerland.;Univ Lausanne, Epalinges, Switzerland..
    Vizcay-Barrena, Gema
    Kings Coll London, Ctr Ultrastructural Imaging, London, England..
    Patel, Ashish
    St Thomas Hosp, Kings Coll London, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Ludwinski, Francesca
    St Thomas Hosp, Kings Coll London, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Padayachee, Soundrie
    Guys & St Thomas Fdn Trust, Dept Ultrason Angiol, London, England..
    Kume, Tsutomu
    Northwestern Univ, Sch Med, Feinberg Cardiovasc Res Inst, Evanston, IL 60208 USA..
    Kwak, Brenda
    Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland..
    Brice, Glen
    St George Hosp, SW Thames Reg Genet Serv, London, England..
    Mansour, Sahar
    St George Hosp, SW Thames Reg Genet Serv, London, England..
    Ostergaard, Pia
    St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England..
    Mortimer, Peter
    St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England..
    Jeffery, Steve
    St Georges Univ London, Cardiovasc & Cell Sci Inst, London, England..
    Brown, Nigel
    St Georges Univ London, Inst Med Biomed Educ, London, England..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Petrova, Tatiana
    CHU Vaudois, Dept Fundamental Oncol, Epalinges, Switzerland.;Univ Lausanne, Epalinges, Switzerland..
    Modarai, Bijan
    St Thomas Hosp, Kings Coll London, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Smith, Alberto
    St Thomas Hosp, Kings Coll London, BHF Ctr Res Excellence, Acad Dept Vasc Surg,Cardiovasc Div, London, England..
    Human Venous Valve Disease Caused by Mutations in FOXC2 and GJC22017In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 54, p. 62-62Article in journal (Other academic)
  • 9.
    Martinez-Corral, Ines
    et al.
    Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
    Mäkinen, Taija
    Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
    Regulation of lymphatic vascular morphogenesis: Implications for pathological (tumor) lymphangiogenesis2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 11, p. 1618-1625Article, review/survey (Refereed)
    Abstract [en]

    Lymphatic vasculature forms the second part of our circulatory system that plays a critical role in tissue fluid homeostasis. Failure of the lymphatic system can lead to excessive accumulation of fluid within the tissue, a condition called lymphedema. Lymphatic dysfunction has also been implicated in cancer metastasis as well as pathogenesis of obesity, atherosclerosis and cardiovascular disease. Since the identification of the first lymphatic marker VEGFR-3 and growth factor VEGF-C almost 20 years ago, a great progress has been made in understanding the mechanisms of lymphangiogenesis. This has been achieved largely through characterization of animal models with specific lymphatic defects and identification of genes causative of human hereditary lymphedema syndromes. In this review we will summarize the current understanding of the regulation of lymphatic vascular morphogenesis, focusing on mechanisms that have been implicated in both developmental and pathological (tumor) lymphangiogenesis.

  • 10.
    Martinez-Corral, Ines
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Frye, Maike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ulvmar, Maria Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Diegez-Hurtado, Rodrigo
    Olmeda, David
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system2016In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 19, no 3, p. 433-445Article in journal (Refereed)
    Abstract [en]

    The lymphatic system is essential in many physiological and pathological processes. Still, much remains to be known about the molecular mechanisms that control its development and function and how to modulate them therapeutically. The study of these mechanisms will benefit from better controlled genetic mouse models targeting specifically lymphatic endothelial cells. Among the genes expressed predominantly in lymphatic endothelium, Vegfr3 was the first one identified and is still considered to be one of the best lymphatic markers and a key regulator of the lymphatic system. Here, we report the generation of a Vegfr3-CreER (T2) knockin mouse by gene targeting in embryonic stem cells. This mouse expresses the tamoxifen-inducible CreER(T2) recombinase under the endogenous transcriptional control of the Vegfr3 gene without altering its physiological expression or regulation. The Vegfr3-CreER (T2) allele drives efficient recombination of floxed sequences upon tamoxifen administration specifically in Vegfr3-expressing cells, both in vitro, in primary lymphatic endothelial cells, and in vivo, at different stages of mouse embryonic development and postnatal life. Thus, our Vegfr3-CreER (T2) mouse constitutes a new powerful genetic tool for lineage tracing analysis and for conditional gene manipulation in the lymphatic endothelium that will contribute to improve our current understanding of this system.

  • 11.
    Martinez-Corral, Ines
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tatin, Florence
    Kizhatil, Krishnakumar
    John, Simon W. M.
    Alitalo, Kari
    Ortega, Sagrario
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Nonvenous Origin of Dermal Lymphatic Vasculature2015In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 116, no 10, p. 1649-1654Article in journal (Refereed)
    Abstract [en]

    Rationale: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. Objective: We aimed to clarify the origin of the murine dermal lymphatic vasculature. Methods and Results: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. Conclusions: Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.

  • 12.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Organ-Specific Origins of Lymphatic Vasculature2015In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, no S1, p. 18-19Article in journal (Other academic)
  • 13. Park, Dae-Young
    et al.
    Lee, Junyeop
    Park, Intae
    Choi, Dongwon
    Lee, Sunju
    Song, Sukhyun
    Hwang, Yoonha
    Hong, Ki Yong
    Nakaoka, Yoshikazu
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kim, Pilhan
    Alitalo, Kari
    Hong, Young-Kwon
    Koh, Gou Young
    Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 3960-3974Article in journal (Refereed)
    Abstract [en]

    Schlemm's canal (SC) is a specialized vascular structure in the eye that functions to drain aqueous humor from the intraocular chamber into systemic circulation. Dysfunction of SC has been proposed to Underlie increased aqueous humor outflow (AHO) resistance, which leads to elevated ocular pressure, a factor for glaucoma development in humans. Here, using lymphatic and blood vasculature reporter mice, we determined that SC, which originates from blood vessels during the postnatal period, acquires lymphatic identity through upregulation of prospero homeobox protein 1 (PROX1), the master regulator of lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin alpha(9) and exhibited continuous vascular endothelial-cadherin (VE-cadherin) junctions and basement membrane, similar to collecting lymphatics. SC notably lacked luminal valves and expression of the lymphatic endothelial cell markers podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Using an ocular puncture model, we determined that reduced AHO altered the fate of SC both during development and under pathologic conditions; however, alteration of VEGF-C/VEGFR3 signaling did not modulate SC integrity and identity. Intriguingly, PROX1 expression levels linearly correlated with SC functionality. For example, PROX1 expression was reduced or undetectable under pathogenic conditions and in deteriorated SCs. Collectively, our data indicate that PROX1 is an accurate and reliable biosensor of SC integrity and identity.

  • 14.
    Potente, Michael
    et al.
    Max Planck Inst Heart & Lung Res, Angiogenesis & Metab Lab, Ludwigstr 43, D-61231 Bad Nauheim, Germany.;Int Inst Mol & Cell Biol, PL-02109 Warsaw, Poland.;DZHK German Ctr Cardiovasc Res, Partner Site Frankfurt, D-13347 Berlin, Germany..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vascular heterogeneity and specialization in development and disease2017In: Nature reviews. Molecular cell biology, ISSN 1471-0072, E-ISSN 1471-0080, Vol. 18, no 8, p. 477-494Article, review/survey (Refereed)
    Abstract [en]

    Blood and lymphatic vessels pervade almost all body tissues and have numerous essential roles in physiology and disease. The inner lining of these networks is formed by a single layer of endothelial cells, which is specialized according to the needs of the tissue that it supplies. Whereas the general mechanisms of blood and lymphatic vessel development are being defined with increasing molecular precision, studies of the processes of endothelial specialization remain mostly descriptive. Recent insights from genetic animal models illuminate how endothelial cells interact with each other and with their tissue environment, providing paradigms for vessel type- and organ-specific endothelial differentiation. Delineating these governing principles will be crucial for understanding how tissues develop and maintain, and how their function becomes abnormal in disease.

  • 15. Rouhani, Sherin J.
    et al.
    Eccles, Jacob D.
    Riccardi, Priscila
    Peske, J. David
    Tewalt, Eric F.
    Cohen, Jarish N.
    Liblau, Roland
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Engelhard, Victor H.
    Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 6771Article in journal (Refereed)
    Abstract [en]

    Lymphatic endothelial cells (LECs) directly express peripheral tissue antigens and induce CD8 T-cell deletional tolerance. LECs express MHC-II molecules, suggesting they might also tolerize CD4 T cells. We demonstrate that when beta-galactosidase (beta-gal) is expressed in LECs, beta-gal-specific CD8 Tcells undergo deletion via the PD-1/PD-L1 and LAG-3/MHC-II pathways. In contrast, LECs do not present endogenous b-gal in the context of MHC-II molecules to b-gal-specific CD4 T cells. Lack of presentation is independent of antigen localization, as membrane-bound haemagglutinin and I-Ea are also not presented by MHC-II molecules. LECs express invariant chain and cathepsin L, but not H2-M, suggesting that they cannot load endogenous antigenic peptides onto MHC-II molecules. Importantly, LECs transfer b-gal to dendritic cells, which subsequently present it to induce CD4 T-cell anergy. Therefore, LECs serve as an antigen reservoir for CD4 T-cell tolerance, and MHC-II molecules on LECs are used to induce CD8 T-cell tolerance via LAG-3.

  • 16.
    Sabine, Amelie
    et al.
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Bovay, Esther
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Demir, Cansaran Saygili
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Kimura, Wataru
    Hamamatsu Univ Sch Med, Hamamatsu, Shizuoka 4313192, Japan..
    Jaquet, Muriel
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Agalarov, Yan
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland..
    Zangger, Nadine
    SIB, Lausanne, Switzerland..
    Scallan, Joshua P.
    Univ Missouri, Columbia, MO USA..
    Graber, Werner
    Univ Bern, Inst Anat, Bern, Switzerland..
    Gulpinar, Elgin
    Harvard Univ, Cambridge, MA USA..
    Kwak, Brenda R.
    Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland.;Univ Geneva, Dept Med Specializat Cardiol, Geneva, Switzerland..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Spanish Natl Canc Res Ctr, Madrid, Spain..
    Ortega, Sagrario
    Spanish Natl Canc Res Ctr, Madrid, Spain..
    Delorenzi, Mauro
    SIB, Lausanne, Switzerland.;Univ Lausanne, Ludwig Ctr Canc Res, Lausanne, Switzerland..
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany..
    Davis, Michael J.
    Univ Missouri, Columbia, MO USA..
    Djonov, Valentin
    Univ Bern, Inst Anat, Bern, Switzerland..
    Miura, Naoyuld
    Hamamatsu Univ Sch Med, Hamamatsu, Shizuoka 4313192, Japan..
    Petrova, Tatiana V.
    CHUV, Dept Fundamental Oncol, CH-1066 Epalinges, Switzerland.;Univ Lausanne, CH-1066 Epalinges, Switzerland.;Ecole Polytech Fed Lausanne, Swiss Canc Res Inst, Lausanne, Switzerland..
    FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 10, p. 3861-3877Article in journal (Refereed)
    Abstract [en]

    Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

  • 17.
    Stanczuk, Lukas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Yang
    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.
    Fruttiger, Marcus
    Adams, Ralf H.
    Saur, Dieter
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Alitalo, Kari
    Graupera, Mariona
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 10, p. 1708-1721Article in journal (Refereed)
    Abstract [en]

    Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110 alpha PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.

  • 18. Tatin, Florence
    et al.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lymphatic vascular morphogenesis2014In: Molecular Mechanisms of Angiogenesis: From Ontogenesis to Oncogenesis, Springer Publishing Company, 2014, p. 25-44Chapter in book (Refereed)
    Abstract [en]

    Lymphatic vessels participate in tissue homeostasis and immune surveillance by draining excess fluid and immune cells from tissues to blood circulation. Impaired lymphatic function can lead to tissue swelling, or lymphoedema, and associated complications, such as chronic inflammation and fat accumulation. The critical role of lymphatic vessels in a number of pathological conditions, including tumour metastasis, has led to an interest in identifying signalling pathways regulating lymphatic vessel development and growth. Here, we review the current knowledge on the molecular mechanisms of lymphatic development and how lymphatic vasculature contributes to diseases.

  • 19.
    Ulvmar, Maria H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Pdgfrb-Cre targets lymphatic endothelial cells of both venous and non-venous origins2016In: Genesis, ISSN 1526-954X, E-ISSN 1526-968X, Vol. 54, no 6, p. 350-358Article in journal (Refereed)
    Abstract [en]

    The Pdgfrb-Cre line has been used as a tool to specifically target pericytes and vascular smooth muscle cells. Recent studies showed additional targeting of cardiac and mesenteric lymphatic endothelial cells (LECs) by the Pdgfrb-Cre transgene. In the heart, this was suggested to provide evidence for a previously unknown non-venous source of LECs originating from yolk sac (YS) hemogenic endothelium (HemEC). Here we show that Pdgfrb-Cre does not, however, target YS HemEC or YS-derived erythro-myeloid progenitors (EMPs). Instead, a high proportion of ECs in embryonic blood vessels of multiple organs, as well as venous derived LECs were targeted. Assessment of temporal Cre activity using the R26-mTmG double reporter suggested recent occurrence of Pdgfrb-Cre recombination in both blood and lymphatic ECs. It thus cannot be excluded that Pdgfrb-Cre mediated targeting of LECs is due to de novo expression of the Pdgfrb-Cre transgene or their previously established venous endothelial origin. Importantly, Pdgfrb-Cre targeting of LECs does not provide evidence for YS HemEC origin of the lymphatic vasculature. Our results highlight the need for careful interpretation of lineage tracing using constitutive Cre lines that cannot discriminate active from historical expression. The early vascular targeting by the Pdgfrb-Cre also warrants consideration for its use in studies of mural cells.

  • 20.
    Ulvmar, Maria H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Heterogeneity in the lymphatic vascular system and its origin2016In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 111, no 4, p. 310-321Article, review/survey (Refereed)
    Abstract [en]

    Lymphatic vessels have historically been viewed as passive conduits for fluid and immune cells, but this perspective is increasingly being revised as new functions of lymphatic vessels are revealed. Emerging evidence shows that lymphatic endothelium takes an active part in immune regulation both by antigen presentation and expression of immunomodulatory genes. In addition, lymphatic vessels play an important role in uptake of dietary fat and clearance of cholesterol from peripheral tissues, and they have been implicated in obesity and arteriosclerosis. Lymphatic vessels within different organs and in different physiological and pathological processes show a remarkable plasticity and heterogeneity, reflecting their functional specialization. In addition, lymphatic endothelial cells (LECs) of different organs were recently shown to have alternative developmental origins, which may contribute to the development of the diverse lymphatic vessel and endothelial functions seen in the adult. Here, we discuss recent developments in the understanding of heterogeneity within the lymphatic system considering the organ-specific functional and molecular specialization of LECs and their developmental origin.

  • 21.
    Vaahtomeri, Kari
    et al.
    Univ Helsinki, Biomedicum Helsinki, Translat Canc Biol Program, Wihuri Res Inst, FI-00014 Helsinki, Finland..
    Karaman, Sinem
    Univ Helsinki, Biomedicum Helsinki, Translat Canc Biol Program, Wihuri Res Inst, FI-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, Biomedicum Helsinki, Translat Canc Biol Program, Wihuri Res Inst, FI-00014 Helsinki, Finland..
    Lymphangiogenesis guidance by paracrine and pericellular factors2017In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, no 16, p. 1615-1634Article, review/survey (Refereed)
    Abstract [en]

    Lymphatic vessels are important for tissue fluid homeostasis, lipid absorption, and immune cell trafficking and are involved in the pathogenesis of several human diseases. The mechanisms by which the lymphatic vasculature network is formed, remodeled, and adapted to physiological and pathological challenges are controlled by an intricate balance of growth factor and biomechanical cues. These transduce signals for the readjustment of gene expression and lymphatic endothelial migration, proliferation, and differentiation. In this review, we describe several of these cues and how they are integrated for the generation of functional lymphatic vessel networks.

  • 22.
    Wang, Yixin
    et al.
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
    Jin, Yi
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortsäter, Henrik
    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. Karolinska Institute.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jakobsson, Lars
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
    Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity2017In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 19, p. 3590-3601Article in journal (Refereed)
    Abstract [en]

    Tissue fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and its role in vessel maturation are unknown. Here, we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, Pdgfb overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and the low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate the requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels, and suggest an ECM-controlled checkpoint that prevents SMC investment of capillaries, which is a common feature in lymphedematous skin.

  • 23. Zarkada, Georgia
    et al.
    Heinolainen, Krista
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kubota, Yoshiaki
    Alitalo, Kari
    VEGFR3 does not sustain retinal angiogenesis without VEGFR22015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 3, p. 761-766Article in journal (Refereed)
    Abstract [en]

    Angiogenesis, the formation of new blood vessels, is regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). VEGFR2 is abundant in the tip cells of angiogenic sprouts, where VEGF/VEGFR2 functions upstream of the delta-like ligand 4 (DLL4)/Notch signal transduction pathway. VEGFR3 is expressed in all endothelia and is indispensable for angiogenesis during early embryonic development. In adults, VEGFR3 is expressed in angiogenic blood vessels and some fenestrated endothelia. VEGFR3 is abundant in endothelial tip cells, where it activates Notch signaling, facilitating the conversion of tip cells to stalk cells during the stabilization of vascular branches. Subsequently, Notch activation suppresses VEGFR3 expression in a negative feedback loop. Here we used conditional deletions and a Notch pathway inhibitor to investigate the cross-talk between VEGFR2, VEGFR3, and Notch in vivo. We show that postnatal angiogenesis requires VEGFR2 signaling also in the absence of Notch or VEGFR3, and that even small amounts of VEGFR2 are able to sustain angiogenesis to some extent. We found that VEGFR2 is required independently of VEGFR3 for endothelial DLL4 up-regulation and angiogenic sprouting, and for VEGFR3 functions in angiogenesis. In contrast, VEGFR2 deletion had no effect, whereas VEGFR3 was essential for postnatal lymphangiogenesis, and even for lymphatic vessel maintenance in adult skin. Knowledge of these interactions and the signaling functions of VEGFRs in blood vessels and lymphatic vessels is essential for the therapeutic manipulation of the vascular system, especially when considering multitargeted antiangiogenic treatments.

  • 24.
    Zhang, Yan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Frye, Maike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alitalo, Kari
    Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 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.
    Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 1296Article in journal (Refereed)
    Abstract [en]

    Incomplete delivery to the target cells is an obstacle for successful gene therapy approaches. Here we show unexpected effects of incomplete targeting, by demonstrating how heterogeneous inhibition of a growth promoting signaling pathway promotes tissue hyperplasia. We studied the function of the lymphangiogenic VEGFR3 receptor during embryonic and post-natal development. Inducible genetic deletion of Vegfr3 in lymphatic endothelial cells (LECs) leads to selection of non-targeted VEGFR3+cells at vessel tips, indicating an indispensable cell-autonomous function in migrating tip cells. Although Vegfr3 deletion results in lymphatic hypoplasia in mouse embryos, incomplete deletion during post-natal development instead causes excessive lymphangiogenesis. Analysis of mosaically targeted endothelium shows that VEGFR3-LECs non-cell-autonomously drive abnormal vessel anastomosis and hyperplasia by inducing proliferation of non-targeted VEGFR3+LECs through cell-contact-dependent reduction of Notch signaling. Heterogeneity in VEGFR3 levels thus drives vessel hyperplasia, which has implications for the understanding of mechanisms of developmental and pathological tissue growth.

  • 25.
    Zhang, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Daubel, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stritt, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 3, article id dev156745Article in journal (Refereed)
    Abstract [en]

    Maintenance of blood vessel integrity is crucial for vascular homeostasis and is mainly controlled at the level of endothelial cell (EC) junctions. Regulation of endothelial integrity has largely been investigated in the mature quiescent vasculature. Less is known about how integrity is maintained during vascular growth and remodeling involving extensive junctional reorganization. Here, we show that embryonic mesenteric blood vascular remodeling is associated with a transient loss of venous integrity and concomitant extravasation of red blood cells (RBCs), followed by their clearance by the developing lymphatic vessels. In wild-type mouse embryos, we observed activated platelets extending filopodia at sites of inter-EC gaps. In contrast, embryos lacking the activatory C-type lectin domain family 1, member b (CLEC1B) showed extravascular platelets and an excessive number of RBCs associated with and engulfed by the first lymphatic EC clusters that subsequently form lumenized blood-filled vessels connecting to the lymphatic system. These results uncover novel functions of platelets in maintaining venous integrity and lymphatic vessels in clearing extravascular RBCs during developmental remodeling of the mesenteric vasculature. They further provide insight into how vascular abnormalities characterized by blood-filled lymphatic vessels arise.

  • 26.
    Zhang, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stritt, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    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.
    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.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alternative lymphatic endothelial progenitor cells compensate for the loss of non-venous-derived progenitors to form mesenteric lymphatic vesselsManuscript (preprint) (Other academic)
1 - 26 of 26
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