Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in ischemic condition is also presented.

Sonic Hedgehog (Shh) is a prototypical angiogenic agent with a crucial role in the regulation of angiogenesis. Experimental studies have shown that Shh is upregulated in response to ischemia. Also, Shh may be found on the surface of circulating microparticles (MPs) and MPs bearing Shh (Shh+ MPs) have shown the ability to contribute to reparative neovascularization after ischemic injury in mice. In this study, the plasma number of Shh+ MPs in patients with peripheral artery disease (PAD) and control subjects without PAD. We found significantly higher number of Shh+ MPs in plasma of subjects with PAD, compared to controls, while the global number of MPs – produced either by endothelial cells, platelets, leukocytes, and erythrocytes – was not different between PAD patients and controls. Interestingly, the concentration of Shh protein unbound to MPs – which was measured in MP-depleted plasma – was not different between subjects with PAD and controls, indicating that, in the setting of PAD, the call for Shh recapitulation does not lead to secretion of protein into the blood but to binding of the protein to the membrane of MPs. These findings provide novel insights on the mechanisms through which the Shh signaling is reactivated during ischemia in humans, with potentially important fundamental and clinical implications.