Nature Medicine
7, 706 - 711 (2001)
doi:10.1038/89083
The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factorsRoberto Pola1, 3, Leona E. Ling2, 3, Marcy Silver1, Michael J. Corbley2, Marianne Kearney1, R. Blake Pepinsky2, Renee Shapiro2, Frederick R. Taylor2, Darren P. Baker2, Takayuki Asahara1
& Jeffrey M. Isner11
Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
2
Biogen Incorporated, Cambridge, Massachusetts, USA
3
R.P. and L.E.L. contributed equally to this study.
Correspondence should be addressed to Jeffrey M. Isner vejeff@aol.comSonic hedgehog (Shh) is a prototypical morphogen known to regulate epithelial/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, characterized 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 isoforms and angiopoietins-1 and -2 from interstitial mesenchymal cells. These findings reveal a novel role for Shh as an indirect angiogenic factor regulating expression of multiple angiogenic cytokines and indicate that Shh might have potential therapeutic use for ischemic disorders.
|
