The axonal attractant Netrin-1 is an angiogenic factor

doi:10.1073/pnas.0405984101

The axonal attractant Netrin-1 is an angiogenic factor

^*Program in Human Molecular Biology and Genetics, Departments of Medicine and Oncological Sciences, and ^‡Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT 84132; and ^†Department of Medicine, Divisions of Hematology and Oncology, Stanford University School of Medicine, Stanford, CA 94305

Edited by Philip W. Majerus, Washington University School of Medicine, St. Louis, MO, and approved October 4, 2004 (received for review August 13, 2004)

Abstract

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.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: dean.li{at}hmbg.utah.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; HUVEC, human umbilical vein endothelial cells; HMVEC, human microvascular endothelial cells; HAEC, human aortic endothelial cells; CAM, chorioallantoic membrane; VSMC, vascular smooth muscle cell.