Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival.
Abstract
RATIONALE:
Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves.
OBJECTIVE:
The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia.
METHODS AND RESULTS:
We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle.
CONCLUSIONS:
This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.
Renault MA1, Chapouly C, Yao Q, Larrieu-Lahargue F, Vandierdonck S, Reynaud A, Petit M, Jaspard-Vinassa B, Belloc I, Traiffort E, Ruat M, Duplàa C, Couffinhal T, Desgranges C, Gadeau AP.
http://circres.ahajournals.org/content/circresaha/112/5/762.full.pdf