title: Resveratrol supplementation abrogates pro-arteriogenic effects of intramyocardial vascular endothelial growth factor in a hypercholesterolemic swine model of chronic ischemia.
abstract: BACKGROUND
  Clinical trials of therapeutic angiogenesis with vascular endothelial growth factor (VEGF) have been disappointing, owing likely to endothelial dysfunction. We used a swine model of chronic ischemia and endothelial dysfunction to determine whether resveratrol coadministration would improve the angiogenic response to VEGF therapy.
  
  
  METHODS
  Yorkshire swine fed a high-cholesterol diet underwent left circumflex ameroid constrictor placement, and were given either no drug (high cholesterol control [HCC], n = 8), perivascular VEGF (2 μg sustained release [high cholesterol VEGF-treated; HCV], n = 8), or VEGF plus oral resveratrol (10 mg/kg, [high cholesterol VEGF- and resveratrol-treated; HCVR], n = 8). After 7 weeks, myocardial contractility, perfusion, and microvessel reactivity in the ischemic territory were assessed. Tissue was analyzed for vessel density, oxidative stress, and protein expression.
  
  
  RESULTS
  Myocardial perfusion was significantly improved in the HCV group compared with the HCC group; resveratrol coadministration abrogated this improvement. There were no differences in regional myocardial contractility between groups. Endothelium-dependent microvessel relaxation was improved in the HCVR group, and endothelium-independent relaxation response was similar between groups. Arteriolar density was greatest in the HCV group, whereas capillary density was similar between groups. Expression of Akt and phospho-endothelial nitric oxide synthase were increased in the HCVR group. Total protein oxidative stress and myeloperoxidase expression were reduced in the HCVR group, but so was the oxidative-stress dependent phosphorylation of vascular endothelial cadherin (VE-cadherin) and β-catenin.
  
  
  CONCLUSIONS
  Although resveratrol coadministration decreases oxidative stress and improves endothelial function, it abolishes improvements in myocardial perfusion and arteriolar density afforded by VEGF treatment alone. This effect is due likely to inhibition of the oxidative stress-dependent phosphorylation of VE-cadherin, an essential step in the initiation of arteriogenesis.
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Chu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Robich
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Lassaletta
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Laham
authors.forename: Thomas
authors.initials: T
authors.lastname: Burgess
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D017023:Coronary Angiography; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D012016:Reference Values; D000077185:Resveratrol; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013267:Stilbenes / Q000008:administration & dosage*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
chemical_list: D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D000077185:Resveratrol