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.
MeSH terms
-
Angiopoietin-1
-
Angiopoietin-2
-
Animals
-
Blood Vessels / anatomy & histology
-
Blood Vessels / physiology
-
Corneal Neovascularization
-
Endothelial Growth Factors / genetics
-
Endothelial Growth Factors / metabolism*
-
Female
-
Genes, Reporter
-
Hedgehog Proteins
-
Hindlimb / blood supply
-
Humans
-
Immunohistochemistry
-
Ischemia / therapy
-
Lymphokines / genetics
-
Lymphokines / metabolism*
-
Male
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / metabolism*
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Myocardium / metabolism
-
Neovascularization, Physiologic / physiology*
-
Patched Receptors
-
Proteins / genetics
-
Proteins / metabolism*
-
Receptors, Cell Surface
-
Recombinant Fusion Proteins / administration & dosage
-
Recombinant Fusion Proteins / metabolism
-
Regional Blood Flow / physiology
-
Signal Transduction*
-
Trans-Activators*
-
Up-Regulation
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
Substances
-
Angiopoietin-1
-
Angiopoietin-2
-
Angpt1 protein, mouse
-
Endothelial Growth Factors
-
Hedgehog Proteins
-
Lymphokines
-
Membrane Glycoproteins
-
Membrane Proteins
-
Patched Receptors
-
Proteins
-
Receptors, Cell Surface
-
Recombinant Fusion Proteins
-
SHH protein, human
-
Trans-Activators
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors