The axonal attractant Netrin-1 is an angiogenic factor.
Blood vessels and nerves often follow parallel trajectories, suggesting that distal targets use common cues that induce vascularization and innervation. Netrins are secreted by the floor plate and attract commissural axons toward the midline of the neural tube. Here, we show that Netrin-1 is also a potent vascular mitogen. Netrin-1 stimulates proliferation, induces migration, and promotes adhesion of endothelial cells and vascular smooth muscle cells with a specific activity comparable to vascular endothelial growth factor and platelet-derived growth factor. Our evidence indicates that the netrin receptor, Neogenin, mediates netrin signaling in vascular smooth muscle cells, but suggests that an unidentified receptor mediates the proangiogenic effects of Netrin-1 on endothelial cells. Netrin-1 also stimulates angiogenesis in vivo and augments the response to vascular endothelial growth factor. Thus, we demonstrate that Netrin-1 is a secreted neural guidance cue with the unique ability to attract both blood vessels and axons, and suggest that other cues may also function as vascular endothelial growth factors.
Park
Kye Won
KW
Program in Human Molecular Biology and Genetics, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Crouse
Dana
D
Lee
Mark
M
Karnik
Satyajit K
SK
Sorensen
Lise K
LK
Murphy
Kelly J
KJ
Kuo
Calvin J
CJ
Li
Dean Y
DY
D042501:Angiogenic Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology*; D001483:Base Sequence; D002417:Cattle; D004247:DNA / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009414:Nerve Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000075388:Netrin-1; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D042501:Angiogenic Proteins; D008565:Membrane Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C091279:neogenin; D000075388:Netrin-1; D004247:DNA