TY - JOUR T1 - Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins JF - Nat Immunol Y1 - 2004 A1 - Karkkainen, Marika J A1 - Haiko, Paula A1 - Sainio, Kirsi A1 - Partanen, Juha A1 - Taipale, Jussi A1 - Petrova, Tatiana V A1 - Jeltsch, Michael A1 - Jackson, David G A1 - Talikka, Marja A1 - Rauvala, Heikki A1 - Betsholtz, Christer A1 - Alitalo, Kari AB - Lymphatic vessels are essential for immune surveillance, tissue fluid homeostasis and fat absorption. Defects in lymphatic vessel formation or function cause lymphedema. Here we show that the vascular endothelial growth factor C (VEGF-C) is required for the initial steps in lymphatic development. In Vegfc-/- mice, endothelial cells commit to the lymphatic lineage but do not sprout to form lymph vessels. Sprouting was rescued by VEGF-C and VEGF-D but not by VEGF, indicating VEGF receptor 3 specificity. The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema. Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development. VL - 5 UR - http://view.ncbi.nlm.nih.gov/pubmed/14634646 IS - 1 JO - Nature Immunology ER - TY - JOUR T1 - Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes JF - FASEB J Y1 - 2002 A1 - Saaristo, Anne A1 - Veikkola, Tanja A1 - Enholm, Berndt A1 - Hytönen, Maija A1 - Arola, Johanna A1 - Pajusola, Katri A1 - Turunen, Païvi A1 - Jeltsch, Michael A1 - Karkkainen, Marika J A1 - Kerjaschki, Dontscho A1 - Bueler, Hansruedi A1 - Ylä-Herttuala, Seppo A1 - Alitalo, Kari AB - Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with hereditary lymphedema. However, VEGF-C can have potent effects on blood vessels because its receptor VEGFR-3 is expressed in certain blood vessels and because the fully processed form of VEGF-C also binds to the VEGFR-2 of blood vessels. To characterize the in vivo effects of VEGF-C on blood and lymphatic vessels, we have overexpressed VEGF-C via adenovirus- and adeno-associated virus-mediated transfection in the skin and respiratory tract of athymic nude mice. This resulted in dose-dependent enlargement and tortuosity of veins, which, along with the collecting lymphatic vessels were found to express VEGFR-2. Expression of angiopoietin 1 blocked the increased leakiness of the blood vessels induced by VEGF-C whereas vessel enlargement and lymphangiogenesis were not affected. However, angiogenic sprouting of new blood vessels was not observed in response to AdVEGF-C or AAV-VEGF-C. These results show that virally produced VEGF-C induces blood vessel changes, including vascular leak, but its angiogenic potency is much reduced compared with VEGF in normal skin. VL - 16 UR - http://view.ncbi.nlm.nih.gov/pubmed/12087065 IS - 9 JO - The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology ER -