Desert Hedgehog Promotes Ischemia-Induced Angiogenesis by Ensuring Peripheral Nerve Survival
Rationale: Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert Hedgehog (Dhh), one of the Hedgehog (Hh) family members, is expressed by Schwann cells of peripheral nerves.
Objective: The purpose of this study is to investigate the contribution of Dhh to angiogenesis in the setting of ischemia.
Methods and Results: We induced hind limb ischemia (HLI) in WT 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 Hh signaling pathway effector Smoothened was specifically invalidated in endothelial cells (ECs), we demonstrated that Dhh does not promote angiogenesis by a direct activation of ECs. 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 VEGFA, Angiopoitein-1 and Neurotrophin-3 in the ischemic muscle.
Conclusions: This study demonstrates the crucial role of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.
- Received January 3, 2013.
- Revision received January 21, 2013.
- Accepted January 23, 2013.
- Copyright © 2013, Circulation Research