title: Vascular endothelial growth factor receptor-2 promotes the development of the lymphatic vasculature.
abstract: Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1(wt/Cre);Vegfr2(flox/flox) mice possess significantly fewer dermal lymphatic vessels than Vegfr2(flox/flox) mice. Although Lyve-1(wt/Cre);Vegfr2(flox/flox) mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1(Cre) mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1(wt/Cre);Vegfr2(flox/flox) embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1(wt/Cre);Vegfr2(flox/flox) mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dellinger
authors.forename: Stryder M
authors.initials: SM
authors.lastname: Meadows
authors.forename: Katherine
authors.initials: K
authors.lastname: Wynne
authors.forename: Ondine
authors.initials: O
authors.lastname: Cleaver
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000196:embryology; D008168:Lung / Q000098:blood supply / Q000196:embryology; D042601:Lymphatic Vessels / Q000196:embryology* / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018919:Neovascularization, Physiologic; D014022:Tissue Survival; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D015017:Yolk Sac / Q000098:blood supply / Q000196:embryology
chemical_list: D006023:Glycoproteins; D026901:Membrane Transport Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; C492273:LYVE1 protein, mouse
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