Figure 1.

Hh in the ischemic skeletal muscle. The upregulation of the Hedgehog (Hh) pathway observed in the ischemic skeletal muscle occurs through unknown mechanisms, perhaps mediated by the Hypoxia Inducible Factor-1α (HIF-1α). Sonic hedgehog (Shh) protein acts on fibroblasts, which respond by producing angiogenic growth factors (including VEGF, HGF, PDGF-BB, IGF), which stimulate proliferation, migration, and survival of endothelial cells (ECs). Shh-responding fibroblasts also produce stromal cell-derived factor 1α (SDF1α), which is responsible for the recruitment of bone marrow-derived endothelial progenitor cells (BM-EPCs) into the ischemic site. Angiogenic growth factors are also produced by peripheral nerves in the ischemic muscle, upon Dhh modulation. There is also evidence that Shh limits the inflammatory response to ischemia in the skeletal muscle. Finally, there is in vitro evidence that ECs may respond to Hh proteins in a direct manner. Such direct stimulation induces EC morphological changes and supports EC tubulogenesis. Dashed lines and italic text represent in vitro data.