Arterial Baroreflex Dysfunction Impairs Ischemia‐Induced Angiogenesis

Abstract

Background Endothelium‐derived acetylcholine ( eAC h) plays an important role in the regulation of vascular actions in response to hypoxia, whereas arterial baroreflex (ABR) dysfunction impairs the eAC h system. We investigated the effects of ABR dysfunction on ischemia‐induced angiogenesis in animal models of hindlimb ischemia with a special focus on eAC h/nicotinic ACh receptor ( nAChR ) signaling activation. Methods and Results Male Sprague‐Dawley rats were randomly assigned to 1 of 3 groups that received (1) sham operation (control group), (2) sinoaortic denervation (SAD)‐induced ABR dysfunction (SAD group), or (3) SAD rats on diet with an acetylcholinesterase inhibitor pyridostigmine (30 mg/kg per day, SAD+Pyr group). After 4 weeks of the SAD intervention, unilateral limb ischemia was surgically induced in all animals. At postoperative day 14, SAD rats exhibited impaired angiogenic action (skin temperature and capillary density) and decreased angiogenic factor expressions (vascular endothelial growth factor [VEGF] and hypoxic inducible factor [HIF]‐1α) in ischemic muscles. These changes were restored by acetylcholinesterase inhibition. Rats with ABR dysfunction had lower eAC h levels than did control rats, and this effect was recovered in SAD+Pyr rats. In α7‐ nAChR knockout mice, pyridostigmine improved ischemia‐induced angiogenic responses and increased the levels of VEGF and HIF‐1α. Moreover, nicotinic receptor blocker inhibited VEGF expression and VEGF receptor 2 phosphorylation (p‐VEGFR2) induced by ACh analog. Conclusions Thus, ABR dysfunction appears to impair ischemia‐induced angiogenesis through the reduction of eAC h/α7‐ nAChR ‐dependent and ‐independent HIF‐1α/VEGF‐VEGFR2 signaling activation.