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Published Online June 29, 2006
Science DOI: 10.1126/science.1124704

Research Articles

Submitted on January 6, 2006
Accepted on May 23, 2006

Netrins Promote Developmental and Therapeutic Angiogenesis

Brent D. Wilson 1, Masaaki Ii 2, Kye Won Park 3, Arminda Suli 4, Lise K. Sorensen 5, Fréderic Larrieu-Lahargue 6, Lisa D. Urness 1, Wonhee Suh 7, Jun Asai 8, Gerhardus A.H. Kock 9, Tina Thorne 8, Marcy Silver 8, Kirk R. Thomas 10, Chi-Bin Chien 11*, Douglas W. Losordo 8*, Dean Y. Li 12*

1 Program in Human Molecular Biology and Genetics; Division of Cardiology
2 Division of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135,USA; Present address: Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan.
3 Program in Human Molecular Biology and Genetics; Department of Oncological Sciences
4 Department of Neurobiology and Anatomy
5 Division of Cardiology
6 Program in Human Molecular Biology and Genetics
7 Program in Human Molecular Biology and Genetics; 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.
8 Division of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135,USA.
9 Division of Cardiovascular Research, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135,USA; Present address: Department of Cardiology, Thoraxcenter, University Medical Center Groningen, University Groningen, Groningen, The Netherlands.
10 Program in Human Molecular Biology and Genetics; Division of Hematology
11 Department of Neurobiology and Anatomy; Brain Institute, University of Utah, Salt Lake City, UT 84112, USA.
12 Department of Oncological Sciences

* To whom correspondence should be addressed.
Chi-Bin Chien , E-mail: chi-bin.chien{at}neuro.utah.edu
Douglas W. Losordo , E-mail: douglas.losordo{at}tufts.edu
Dean Y. Li , E-mail: dean.li{at}hmbg.utah.edu

Axonal guidance and vascular patterning share several guidance cues, including proteins of the netrin family. We demonstrate that netrins stimulate the proliferation, migration and tube formation of human endothelial cells in vitro, and that this stimulation is independent of known netrin receptors. Knockdown of netrin1a mRNA in zebrafish inhibits vascular sprouting, implying a pro-angiogenic 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.


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