Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
Surgery. 2011 Sep;150(3):390-9. doi: 10.1016/j.surg.2011.06.009. Epub 2011 Jul 23.
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.
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.
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.
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.
血管内皮生长因子（VEGF）治疗性血管生成的临床试验令人失望，这可能是由于内皮功能障碍。我们使用慢性缺血和内皮功能障碍的猪模型来确定白藜芦醇联合治疗是否会改善 VEGF 治疗的血管生成反应。
给予高脂饮食的约克夏猪进行左回旋支动脉缩窄环放置，并给予以下药物：无药物（高胆固醇对照组 [HCC]，n = 8）、血管周围 VEGF（2μg 持续释放 [高胆固醇 VEGF 治疗组；HCV，n = 8）或 VEGF 加口服白藜芦醇（10mg/kg，[高胆固醇 VEGF 和白藜芦醇治疗组；HCVR，n = 8）。7 周后，评估缺血区心肌收缩力、灌注和微血管反应。分析组织血管密度、氧化应激和蛋白表达。
与 HCC 组相比，HCV 组心肌灌注明显改善；白藜芦醇联合治疗消除了这种改善。各组间局部心肌收缩力无差异。HCVR 组内皮依赖性微血管松弛改善，各组间内皮非依赖性松弛反应相似。HCV 组的小动脉密度最大，而毛细血管密度各组间相似。HCVR 组 Akt 和磷酸化内皮型一氧化氮合酶的表达增加。HCVR 组总蛋白氧化应激和髓过氧化物酶表达降低，但血管内皮钙黏蛋白（VE-cadherin）和β-连环蛋白的氧化应激依赖性磷酸化也降低。
尽管白藜芦醇联合治疗可降低氧化应激并改善内皮功能，但它会消除 VEGF 单独治疗带来的心肌灌注和小动脉密度的改善。这种作用可能是由于抑制了 VE-cadherin 的氧化应激依赖性磷酸化，这是动脉生成启动的关键步骤。
