title: Microparticles carrying Sonic hedgehog favor neovascularization through the activation of nitric oxide pathway in mice.
abstract: BACKGROUND
  Microparticles (MPs) are vesicles released from plasma membrane upon cell activation and during apoptosis. Human T lymphocytes undergoing activation and apoptosis generate MPs bearing morphogen Shh (MPs(Shh+)) that are able to regulate in vitro angiogenesis.
  
  
  RESULTS
  Here, we investigated the ability of MPs(Shh+) to modulate neovascularization in a model of mouse hind limb ischemia. Mice were treated in vivo for 21 days with vehicle, MPs(Shh+), MPs(Shh+) plus cyclopamine or cyclopamine alone, an inhibitor of Shh signalling. Laser doppler analysis revealed that the recovery of the blood flow was 1.4 fold higher in MPs(Shh+)-treated mice than in controls, and this was associated with an activation of Shh pathway in muscles and an increase in NO production in both aorta and muscles. MPs(Shh+)-mediated effects on flow recovery and NO production were completely prevented when Shh signalling was inhibited by cyclopamine. In aorta, MPs(Shh+) increased activation of eNOS/Akt pathway, and VEGF expression, being inhibited by cyclopamine. By contrast, in muscles, MPs(Shh+) enhanced eNOS expression and phosphorylation and decreased caveolin-1 expression, but cyclopamine prevented only the effects of MPs(Shh+) on eNOS pathway. Quantitative RT-PCR revealed that MPs(Shh+) treatment increased FGF5, FGF2, VEGF A and C mRNA levels and decreased those of α5-integrin, FLT-4, HGF, IGF-1, KDR, MCP-1, MT1-MMP, MMP-2, TGFβ1, TGFβ2, TSP-1 and VCAM-1, in ischemic muscles.
  
  
  CONCLUSIONS
  These findings suggest that MPs(Shh+) may contribute to reparative neovascularization after ischemic injury by regulating NO pathway and genes involved in angiogenesis.
authors.affiliation: CNRS, UMR 6214, INSERM, U771, Université d'Angers, Faculté de Médecine, Angers, France.
authors.forename: Tarek
authors.initials: T
authors.lastname: Benameur
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soleti
authors.forename: Chiara
authors.initials: C
authors.lastname: Porro
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Martínez
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D004195:Disease Models, Animal; D005121:Extremities / Q000098:blood supply; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D009569:Nitric Oxide