title: A differential role for nitric oxide in two forms of physiological angiogenesis in mouse.
abstract: NO plays a role in a variety of in vitro models of angiogenesis, although confounding effects of NO on non-endothelial tissues make its role during in vivo angiogenesis unclear. We therefore examined the effects of NO on two physiological models of angiogenesis in mouse skeletal muscle: (1) administration of prazosin (50 mg l-1) thereby increasing blood flow; and (2) muscle overload from surgical ablation of a functional synergist. These models induce angiogenesis via longitudinal splitting and capillary sprouting, respectively. Administration of NG-nitro-L-arginine (L-NNA) abolished the increase in capillary to fibre ratio (C:F) in response to prazosin administration, along with the increases in luminal filopodia and large endothelial vacuoles. L-NNA prevented luminal filopodia and vacuolisation in response to extirpation, but had no effect on abluminal sprouting, and little effect on C:F. Comparison of mice lacking endothelial (eNOS-/-) and neuronal NO synthase (nNOS-/-) showed that longitudinal splitting is eNOS-dependent, and Western blotting demonstrated an increase in eNOS but not inducible NOS (iNOS) expression. These data show that there are two pathways of physiological angiogenesis in skeletal muscle characterised by longitudinal splitting and capillary sprouting, respectively. NO generated by eNOS plays an essential role in splitting but not in sprouting angiogenesis, which has important implications for angiogenic therapies that target NO.
authors.affiliation: Angiogenesis Research Group, Centre for Cardiovascular Sciences, The University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: James L
authors.initials: JL
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Cartland
authors.forename: Arif
authors.initials: A
authors.lastname: Hussain
authors.forename: Stuart
authors.initials: S
authors.lastname: Egginton
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002196:Capillaries / Q000502:physiology / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D011224:Prazosin