title: The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors.
abstract: Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial/mesenchymal interactions during embryonic development. We found that the hedgehog-signaling pathway is present in adult cardiovascular tissues and can be activated in vivo. Shh was able to induce robust angiogenesis, characterized by distinct large-diameter vessels. Shh also augmented blood-flow recovery and limb salvage following operatively induced hind-limb ischemia in aged mice. In vitro, Shh had no effect on endothelial-cell migration or proliferation; instead, it induced expression of two families of angiogenic cytokines, including all three vascular endothelial growth factor-1 isoforms and angiopoietins-1 and -2 from interstitial mesenchymal cells. These findings reveal a novel role for Shh as an indirect angiogenic factor regulating expression of multiple angiogenic cytokines and indicate that Shh might have potential therapeutic use for ischemic disorders.
authors.affiliation: Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pola
authors.forename: L E
authors.initials: LE
authors.lastname: Ling
authors.forename: M
authors.initials: M
authors.lastname: Silver
authors.forename: M J
authors.initials: MJ
authors.lastname: Corbley
authors.forename: M
authors.initials: M
authors.lastname: Kearney
authors.forename: R
authors.initials: R
authors.lastname: Blake Pepinsky
authors.forename: R
authors.initials: R
authors.lastname: Shapiro
authors.forename: F R
authors.initials: FR
authors.lastname: Taylor
authors.forename: D P
authors.initials: DP
authors.lastname: Baker
authors.forename: T
authors.initials: T
authors.lastname: Asahara
authors.forename: J M
authors.initials: JM
authors.lastname: Isner
mesh_terms: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D001808:Blood Vessels / Q000033:anatomy & histology / Q000502:physiology; D016510:Corneal Neovascularization; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D053823:Hedgehog Proteins; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007150:Immunohistochemistry; D007511:Ischemia / Q000628:therapy; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000072079:Patched Receptors; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D053823:Hedgehog Proteins; D008222:Lymphokines; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors