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Science 313 (5787): 640-644

Copyright © 2006 by the American Association for the Advancement of Science

Netrins Promote Developmental and Therapeutic Angiogenesis

Brent D. Wilson,1,2* Masaaki Ii,7*{dagger} Kye Won Park,1,3* Arminda Suli,4* Lise K. Sorensen,2 Fréderic Larrieu-Lahargue,1 Lisa D. Urness,1,2 Wonhee Suh,1{ddagger} Jun Asai,7 Gerhardus A.H. Kock,7§ Tina Thorne,7 Marcy Silver,7 Kirk R. Thomas,1,5 Chi-Bin Chien,4,6|| Douglas W. Losordo,7|| Dean Y. Li3||

Abstract: Axonal guidance and vascular patterning share several guidance cues, including proteins in the netrin family. We demonstrate that netrins stimulate proliferation, migration, and tube formation of human endothelial cells in vitro and that this stimulation is independent of known netrin receptors. Suppression of netrin1a messenger RNA in zebrafish inhibits vascular sprouting, implying a proangiogenic role for netrins during vertebrate development. We also show that netrins accelerate neovascularization in an in vivo model of ischemia and that they reverse neuropathy and vasculopathy in a diabetic murine model. We propose that the attractive vascular and neural guidance functions of netrins offer a unique therapeutic potential.

1 Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112, USA.
2 Division of Cardiology, University of Utah, Salt Lake City, UT 84112, USA.
3 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
4 Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA.
5 Division of Hematology, University of Utah, Salt Lake City, UT 84112, USA.
6 Brain Institute, University of Utah, Salt Lake City, UT 84112, USA.
7 Division of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.

* These authors contributed equally to this work.

{dagger} Present address: Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.

{ddagger} Present address: Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-Ku, Seoul 135-710, Korea.

§ Present address: Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University Groningen, 30.001 Groningen, Netherlands.

|| To whom correspondence should be addressed. E-mail: dean.li{at}hmbg.utah.edu (D.Y.L.); douglas.losordo{at}tufts.edu (D.W.L.); chi-bin.chien{at}neuro.utah.edu (C.B.C)

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