title: Arterial baroreflex dysfunction impairs ischemia-induced angiogenesis.
abstract: BACKGROUND
  Endothelium-derived acetylcholine (eACh) plays an important role in the regulation of vascular actions in response to hypoxia, whereas arterial baroreflex (ABR) dysfunction impairs the eACh system. We investigated the effects of ABR dysfunction on ischemia-induced angiogenesis in animal models of hindlimb ischemia with a special focus on eACh/nicotinic ACh receptor (nAChR) signaling activation.
  
  
  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 eACh 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 eACh/α7-nAChR-dependent and -independent HIF-1α/VEGF-VEGFR2 signaling activation.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Changning
authors.initials: C
authors.lastname: Hao
authors.forename: Zhen-Hao
authors.initials: ZH
authors.lastname: Huang
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Song
authors.forename: Yi-Qin
authors.initials: YQ
authors.lastname: Shi
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Duan
mesh_terms: D000818:Animals; D001158:Arteries / Q000502:physiology*; D017704:Baroreflex / Q000502:physiology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D005121:Extremities / Q000098:blood supply; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011729:Pyridostigmine Bromide / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D002800:Cholinesterase Inhibitors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D011729:Pyridostigmine Bromide
keywords: acetylcholinesterase inhibitor; angiogenesis; arterial baroreflex; non‐neural cholinergic system; peripheral vascular disease