title: Pleiotropic beneficial effects of sonic hedgehog gene therapy in an experimental model of peripheral limb ischemia.
abstract: We have previously shown that the signaling pathway of the embryonic morphogen Sonic hedgehog (Shh) is recapitulated in the postnatal skeletal muscle in response to ischemia. We have also demonstrated that Shh is an indirect angiogenic agent upregulating various families of angiogenic growth factors and that Shh gene therapy improves angiogenesis and heart function in experimental models of myocardial ischemia. Based on these findings, we hypothesized that Shh gene therapy is beneficial in an experimental model of peripheral ischemia. We found that intramuscular (i.m.) treatment with a plasmid encoding the Shh human gene (phShh) increased blood flow, capillary density, and arteriole density in mice in which peripheral circulation of the hindlimb was disrupted by removal of the common femoral artery. Shh gene therapy also enhanced vasculogenesis, by increasing the number of circulating bone marrow (BM)-derived endothelial precursors and improving the contribution of these cells to the process of neovascularization. Finally, phShh treatment induced upregulation of prototypical angiogenic, arteriogenic, and vasculogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietin 1 (Ang-1), and stromal cell-derived factor-1 (SDF-1α). These data suggest that Shh gene therapy merits further investigation for its ability to trigger the expression of potent trophic factors and stimulate pleiotropic aspects of neovascularization in the setting of ischemia.
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Palladino
authors.forename: Ilaria
authors.initials: I
authors.lastname: Gatto
authors.forename: Valentina
authors.initials: V
authors.lastname: Neri
authors.forename: Stefania
authors.initials: S
authors.lastname: Straino
authors.forename: Marcy
authors.initials: M
authors.lastname: Silver
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tritarelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Piccioni
authors.forename: Roy C
authors.initials: RC
authors.lastname: Smith
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gaetani
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
authors.forename: Maurizio
authors.initials: M
authors.lastname: Capogrossi
authors.forename: Roberto
authors.initials: R
authors.lastname: Pola
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D053823:Hedgehog Proteins; D042461:Vascular Endothelial Growth Factor A