title: Semaphorin 6A regulates angiogenesis by modulating VEGF signaling.
abstract: Formation of new vessels during development and in the mature mammal generally proceeds through angiogenesis. Although a variety of molecules and signaling pathways are known to underlie endothelial cell sprouting and remodeling during angiogenesis, many aspects of this complex process remain unexplained. Here we show that the transmembrane semaphorin6A (Sema6A) is expressed in endothelial cells, and regulates endothelial cell survival and growth by modulating the expression and signaling of VEGFR2, which is known to maintain endothelial cell viability by autocrine VEGFR signaling. The silencing of Sema6A in primary endothelial cells promotes cell death that is not rescued by exogenous VEGF-A or FGF2, attributable to the loss of prosurvival signaling from endogenous VEGF. Analyses of mouse tissues demonstrate that Sema6A is expressed in angiogenic and remodeling vessels. Mice with null mutations of Sema6A exhibit significant defects in hyaloid vessels complexity associated with increased endothelial cell death, and in retinal vessels development that is abnormally reduced. Adult Sema6A-null mice exhibit reduced tumor, matrigel, and choroidal angiogenesis compared with controls. Sema6A plays important roles in development of the nervous system. Here we show that it also regulates vascular development and adult angiogenesis.
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda MD 20892, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Segarra
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Ohnuki
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.forename: Ombretta
authors.initials: O
authors.lastname: Salvucci
authors.forename: Xu
authors.initials: X
authors.lastname: Hou
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Xuri
authors.initials: X
authors.lastname: Li
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002829:Choroid / Q000098:blood supply; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D039961:Semaphorins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C504203:Sema6a protein, mouse; D039961:Semaphorins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D040301:Vascular Endothelial Growth Factor Receptor-2