Anti-angiogenic effect of high-dose resveratrol in a swine model of metabolic syndrome.
BACKGROUND
Resveratrol has been reported to induce angiogenesis in ischemic tissue. We hypothesized that high-dose resveratrol would improve native angiogenesis in a swine model of metabolic syndrome and chronic myocardial ischemia.


METHODS
Yorkshire swine were fed a normal diet (Control, n = 7), hypercholesterolemic diet (HCD, n = 7), or hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/day orally, HCD-R; n = 7) beginning 1 month prior to surgery. Chronic ischemia was created by placing an ameroid constrictor on the left circumflex coronary artery. After 7 weeks, swine underwent functional MRI, coronary angiography, and serum and heart tissue harvest for analysis.


RESULTS
HCD-R animals had lower body mass index (P < .001), total cholesterol (P < .001), low-density lipoprotein (LDL; P < .001), blood glucose levels (P < .001), and systolic blood pressure (P = .03) than HCD animals. There was no difference in regional myocardial function at 7 weeks (P = .25). Coronary angiograms revealed no difference in Rentrop collateral scores (P = .68). Staining for platelet endothelial cell adhesion molecule-1 demonstrated higher capillary density in the Control group (versus HCD and HCD-R; P = .02). Immunoblotting demonstrated decreased expression of the pro-angiogenic protein vascular endothelial (VE)-cadherin (P = .002) and an increase in anti-angiogenic proteins angiostatin (P = .001) and thrombospondin (P = .02) in the HCD and HCD-R groups. Matrix metalloprotease 2 (MMP 2; P = .47) and MMP 9 (P = .12) were not different among groups.


CONCLUSIONS
Supplemental resveratrol positively modified cardiovascular risk factors including body mass index, cholesterol, glucose tolerance, and systolic blood pressure. However, it did not increase native collateral formation in the ischemic myocardium. This may be a result of increased angiostatin and thrombospondin leading to decreased expression of VE-cadherin and other pro-angiogenic factors.
Robich
Michael P
MP
Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Chu
Louis M
LM
Chaudray
Mirnal
M
Nezafat
Reza
R
Han
Yuchi
Y
Clements
Richard T
RT
Laham
Roger J
RJ
Manning
Warren J
WJ
Coady
Michael A
MA
Sellke
Frank W
FW
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D043168:Angiostatins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003097:Collateral Circulation / Q000187:drug effects; D017023:Coronary Angiography; D004195:Disease Models, Animal; D008279:Magnetic Resonance Imaging; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage*; D013552:Swine; D013556:Swine, Miniature; D000099152:Cadherin 5
D020533:Angiogenesis Inhibitors; D043168:Angiostatins; D015703:Antigens, CD; D015820:Cadherins; D002791:Cholesterol, Dietary; D000077185:Resveratrol; D013267:Stilbenes; D000099152:Cadherin 5