title: Semaphorin 4A exerts a proangiogenic effect by enhancing vascular endothelial growth factor-A expression in macrophages.
abstract: The axon guidance cues semaphorins (Semas) and their receptors plexins have been shown to regulate both physiological and pathological angiogenesis. Sema4A plays an important role in the immune system by inducing T cell activation, but to date, the role of Sema4A in regulating the function of macrophages during the angiogenic and inflammatory processes remains unclear. In this study, we show that macrophage activation by TLR ligands LPS and polyinosinic-polycytidylic acid induced a time-dependent increase of Sema4A and its receptors PlexinB2 and PlexinD1. Moreover, in a thioglycollate-induced peritonitis mouse model, Sema4A was detected in circulating Ly6C(high) inflammatory monocytes and peritoneal macrophages. Acting via PlexinD1, exogenous Sema4A strongly increased macrophage migration. Of note, Sema4A-activated PlexinD1 enhanced the expression of vascular endothelial growth factor-A, but not of inflammatory chemokines. Sema4A-stimulated macrophages were able to activate vascular endothelial growth factor receptor-2 and the PI3K/serine/threonine kinase Akt pathway in endothelial cells and to sustain their migration and in vivo angiogenesis. Remarkably, in an in vivo cardiac ischemia/reperfusion mouse model, Sema4A was highly expressed in macrophages recruited at the injured area. We conclude that Sema4A activates a specialized and restricted genetic program in macrophages able to sustain angiogenesis and participates in their recruitment and activation in inflammatory injuries.
authors.affiliation: Department of Oncological Sciences, University of Torino School of Medicine, 10060 Candiolo, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Meda
authors.forename: Fabiola
authors.initials: F
authors.lastname: Molla
authors.forename: Maria
authors.initials: M
authors.lastname: De Pizzol
authors.forename: Donatella
authors.initials: D
authors.lastname: Regano
authors.forename: Federica
authors.initials: F
authors.lastname: Maione
authors.forename: Stefania
authors.initials: S
authors.lastname: Capano
authors.forename: Massimo
authors.initials: M
authors.lastname: Locati
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
mesh_terms: D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D039961:Semaphorins / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C519231:Plxnb2 protein, mouse; C473552:Plxnd1 protein, mouse; C534721:Sema4A protein, mouse; D039961:Semaphorins; D042461:Vascular Endothelial Growth Factor A