Published Online
on July 14, 2003

A more recent version of this article appeared on July 29, 2003

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Submitted on December 18, 2002
Revised on April 10, 2003
Accepted on April 14, 2003

Postnatal Recapitulation of Embryonic Hedgehog Pathway in Response to Skeletal Muscle Ischemia

Roberto Pola MD, PhD, Leona E. Ling PhD, Tamar R. Aprahamian BS, Elena Barban MD, Marta Bosch-Marce PhD, Cynthia Curry BS, Michael Corbley PhD, Marianne Kearney BS, Jeffrey M. Isner MD, and Douglas W. Losordo MD^*

From the Department of Medicine (Cardiovascular Research), St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass (R.P., T.R.A., E.B., M.B.-M., C.C., M.K., J.M.I., D.W.L.); the Department of Medicine, A. Gemelli University Hospital, Rome, Italy (R.P.); and Biogen, Inc, Cambridge, Mass (L.E.L., M.C.).

^* To whom correspondence should be addressed. E-mail: douglas.losordo{at}tufts.edu.

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.

Methods and 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.

Key words: genes, hedgehog • ischemia • muscle, skeletal • angiogenesis • tissue regeneration

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