Author:

Keywords:

Animals, Collagen, Drug Combinations, Endothelium, Vascular, Laminin, Mice, Mice, Mutant Strains, Neovascularization, Pathologic, Nerve Growth Factors, Proteoglycans, Pseudopodia, Rats, Receptors, Cell Surface, Tumor Suppressor Proteins, Science & Technology, Life Sciences & Biomedicine, Cell Biology, Developmental Biology, Genetics & Heredity, vessel guidance, axon guidance molecules, tip cell, neovascularization, tumor angiogenesis, COLORECTAL-CANCER DCC, C-ELEGANS, BASEMENT-MEMBRANE, AXON GUIDANCE, GENE, EXPRESSION, CELLS, MOUSE, VEGF, MECHANISMS, Netrin Receptors, Netrin-1, 06 Biological Sciences, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, 31 Biological sciences, 32 Biomedical and clinical sciences, 52 Psychology

Abstract:

Netrins are secreted molecules with roles in axonal growth and angiogenesis. The Netrin receptor UNC5B is required during embryonic development for vascular patterning, suggesting that it may also contribute to postnatal and pathological angiogenesis. Here we show that unc5b is down-regulated in quiescent adult vasculature, but re-expressed during sprouting angiogenesis in matrigel and tumor implants. Stimulation of UNC5B-expressing neovessels with an agonist (Netrin-1) inhibits sprouting angiogenesis. Genetic loss of function of unc5b reduces Netrin-1-mediated angiogenesis inhibition. Expression of UNC5B full-length receptor also triggers endothelial cell repulsion in response to Netrin-1 in vitro, whereas a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion. These data show that UNC5B activation inhibits sprouting angiogenesis, thus identifying UNC5B as a potential anti-angiogenic target.