The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors

Sonic hedgehog (Shh) is a prototypical morphogen known to regulate epitheli al/mesenchymal interactions during embryonic development. We found that the hedgehog-signaling pathway is present in adult cardiovascular tissues and can be activated in vivo. Shh was able to induce robust angiogenesis, chara cterized by distinct large-diameter vessels. Shh also augmented blood-flow recovery and limb salvage following operatively induced hind-limb ischemia in aged mice. In vitro, Shh had no effect on endothelial-cell migration or proliferation; instead, it induced expression of two families of angiogenic cytokines, including all three vascular endothelial growth factor-1 isofor ms and angiopoietins-1 and -2 from interstitial mesenchymal cells. These fi ndings reveal a novel role for Shh as an indirect angiogenic factor regulat ing expression of multiple angiogenic cytokines and indicate that Shh might have potential therapeutic use for ischemic disorders.