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Postnatal Recapitulation of Embryonic Hedgehog Pathway in Response to Skeletal Muscle Ischemia
- Source :
- Circulation. 108:479-485
- Publication Year :
- 2003
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2003.
-
Abstract
- 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.
- Subjects :
- Male
Patched Receptors
Vascular Endothelial Growth Factor A
Patched
medicine.medical_specialty
Angiogenesis
Blotting, Western
Neovascularization, Physiologic
Mice, Transgenic
Receptors, Cell Surface
Endothelial Growth Factors
Biology
Mesoderm
Mice
chemistry.chemical_compound
Downregulation and upregulation
Ischemia
Physiology (medical)
Internal medicine
medicine
Animals
Hedgehog Proteins
RNA, Messenger
Antibodies, Blocking
Muscle, Skeletal
Hedgehog
Lymphokines
Vascular Endothelial Growth Factors
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Immunohistochemistry
Hedgehog signaling pathway
Hindlimb
Up-Regulation
Cell biology
Mice, Inbred C57BL
Patched-1 Receptor
Vascular endothelial growth factor
Disease Models, Animal
Vascular endothelial growth factor A
Endocrinology
chemistry
Trans-Activators
Intercellular Signaling Peptides and Proteins
Female
Cardiology and Cardiovascular Medicine
Signal Transduction
Subjects
Details
- ISSN :
- 15244539 and 00097322
- Volume :
- 108
- Database :
- OpenAIRE
- Journal :
- Circulation
- Accession number :
- edsair.doi.dedup.....41d589701a32d770d0e2492a01637d98