Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia.
BACKGROUND
Hedgehog (Hh) proteins are morphogens regulating epithelial-mesenchymal signaling during several crucial processes of embryonic development, including muscle patterning. Sonic (Shh), Indian (Ihh), and Desert (Dhh) hedgehog constitute the repertoire of Hh genes in humans. The activities of all 3 are transduced via the Patched (Ptc1) receptor. Recent observations indicate that exogenous administration of Shh induces angiogenesis. Here, we studied whether the endogenous Hh pathway, in addition to its functions during embryogenesis, plays a physiological role in muscle regeneration after ischemia in adults.


RESULTS
We found that skeletal muscle ischemia induces strong local upregulation of Shh mRNA and protein. In addition, the Ptc1 receptor is activated in interstitial mesenchymal cells within the ischemic area, indicating that these cells respond to Shh and that the Shh pathway is functional. We also found that Shh-responding cells produce vascular endothelial growth factor under ischemic conditions and that systemic treatment with a Shh-blocking antibody inhibits the local angiogenic response and the upregulation of vascular endothelial growth factor.


CONCLUSIONS
Our study shows that the Hh signaling may be recapitulated postnatally in adult and fully differentiated muscular tissues and has a regulatory role on angiogenesis during muscle regeneration after ischemia. These findings demonstrate a novel biological activity for the Hh pathway with both fundamental and potential therapeutic implications.
Pola
Roberto
R
Department of Medicine (Cardiovascular Research), St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135-2997, USA.
Ling
Leona E
LE
Aprahamian
Tamar R
TR
Barban
Elena
E
Bosch-Marce
Marta
M
Curry
Cynthia
C
Corbley
Michael
M
Kearney
Marianne
M
Isner
Jeffrey M
JM
Losordo
Douglas W
DW
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015153:Blotting, Western; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005260:Female; D053823:Hedgehog Proteins; D006614:Hindlimb / Q000098:blood supply / Q000503:physiopathology; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D019138:Antibodies, Blocking; D016228:Endothelial Growth Factors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008222:Lymphokines; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors