Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor.
Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF- but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGF- but not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a function-blocking Nrp-1 antibody. While both Sema3A- and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF- but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.
Acevedo
Lisette M
LM
Department of Pathology and Moores UCSD Cancer Center, University of California-San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
Barillas
Samuel
S
Weis
Sara M
SM
Göthert
Joachim R
JR
Cheresh
David A
DA
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D002645:Chickens; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D039942:Neuropilin-1 / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D040121:Semaphorin-3A / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D039942:Neuropilin-1; D016392:Proto-Oncogene Proteins pp60(c-src)