title: Repulsive axon guidance molecule Slit3 is a novel angiogenic factor.
abstract: Slits are large, secreted repulsive axon guidance molecules. Recent genetic studies revealed that the Slit3 is dispensable for neural development but required for non-neuron-related developmental processes, such as the genesis of the diaphragm and kidney. Here we report that Slit3 potently promotes angiogenesis, a process essential for proper organogenesis during embryonic development. We observed that Slit3 is expressed and secreted by both endothelial cells and vascular smooth muscle cells in vasculature and that the Slit cognate receptors Robo1 and Robo4 are universally expressed by endothelial cells, suggesting that Slit3 may act in paracrine and autocrine manners to regulate endothelial cells. Cellular function studies revealed that Slit3 stimulates endothelial-cell proliferation, promotes endothelial-cell motility and chemotaxis via interaction with Robo4, and accelerates endothelial-cell vascular network formation in vitro with a specific activity comparable with vascular endothelial growth factor. Furthermore, Slit3 stimulates neovessel sprouting ex vivo and new blood vessel growth in vivo. Consistent with these observations, the Slit3 knockout mice display disrupted angiogenesis during embryogenesis. Taken together, our studies reveal that the repulsive axon guidance molecule Slit3 is a novel and potent angiogenic factor and functions to promote angiogenesis in coordinating organogenesis during embryonic development.
authors.affiliation: Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602-4712, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Ursula M
authors.initials: UM
authors.lastname: Dietrich
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Geng
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.forename: Lianchun
authors.initials: L
authors.lastname: Wang
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology*; D002460:Cell Line; D002642:Chick Embryo; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000097905:Roundabout Proteins
chemical_list: D042501:Angiogenic Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D020741:rho GTP-Binding Proteins; D000097905:Roundabout Proteins; C462951:ROBO4 protein, human; C578845:Robo4 protein, rat; C498990:SLIT3 protein, human; C432251:Slit3 protein, mouse; C467484:VEGFA protein, human