Expression of VEGF and angiopoietins-1 and -2 during ischemia-induced coronary angiogenesis
Expression of VEGF and angiopoietins-1 and -2 during ischemia-induced coronary angiogenesis
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DOI：
10.1152/ajpheart.00621.2002
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发表时间：
2003-07-01
影响因子：
4.8
通讯作者：
Chilian, WM
中科院分区：
文献类型：
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作者：
Matsunaga, T;Warltier, DC;Chilian, WM
缺血时冠状动脉毛细血管生长的机制尚不清楚。我们假设血管内皮生长因子（VEGF）和血管生成素（Ang）/Tie-2的表达参与了毛细血管生长作为对缺血的适应。为了验证这一假设，我们测量了毛细血管密度，VEGF，Ang-1，Ang-2和Tie-2受体的表达及其磷酸化状态在心肌缺血的反复发作在慢性仪器犬。通过多次（1次/小时; 8次/天）短暂（2分钟）闭塞左前降支冠状动脉1、7、14或21天诱导反复缺血发作。假手术组接受与实验组相同的器械，但不接受闭塞方案。侧支血流量（微球）在第21天从9 +/- 3逐渐增加到83 +/- 10 ml.min（-1. 100 g（-1））。毛细血管密度在第7天从2，378 +/- 53（假手术）增加到2，962 +/- 60/mm（2），但在第21天下降到2，594 +/- 39/mm（2）。心肌间质液中VEGF和Ang-2的表达（Western分析）在重复闭塞的第3天达到峰值，但此后逐渐减弱。相反，血管紧张素-1的表达在闭塞组中始终保持相对恒定。在假手术组中，VEGF和Ang-2的表达较低，并且在所有时间都是恒定的。Tie-2磷酸化水平在缺血后第7天降低，第21天升高（P < 0.05）。我们的研究结果表明，毛细血管密度增加心肌缺血，但发展后的侧支循环和恢复流动到缺血区，毛细血管密度恢复到控制水平。毛细血管密度的变化与VEGF和Ang-2表达相关，但与Tie-2磷酸化呈负相关。我们推测冠状动脉血管生成是一个协调的事件，涉及VEGF和Ang-2的表达，治疗性血管生成策略可能最终需要使用多种因子进行治疗。
The mechanisms underlying coronary capillary growth in response to ischemia are undefined. We hypothesized that the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)/Tie-2 were involved in capillary growth as an adaptation to ischemia. To test this hypothesis we measured capillary density, and the expressions of VEGF, Ang-1, Ang-2, and the Tie-2 receptor and its phosphorylation state during repetitive episodes of myocardial ischemia in chronically instrumented canines. Repetitive episodes of ischemia were induced by multiple (once/ hour; 8/day), brief (2 min) occlusions of the left anterior descending coronary artery for 1, 7, 14, or 21 days. A sham group received the same instrumentation as the experimental groups but not the occlusion protocol. Collateral blood flow ( microspheres) progressively increased from 9 +/- 3 to 83 +/- 10 ml.min(-1).100 g(-1) on day 21. Capillary density increased at day 7 from 2,378 +/- 53 ( sham) to 2,962 +/- 60/mm(2), but it decreased to 2,594 +/- 39/mm(2) at day 21. Both VEGF and Ang-2 expression in myocardial interstitial fluid ( Western analyses) peaked at day 3 of the repetitive occlusions but waned thereafter. In contrast the expression of Ang-1 remained relatively constant at all times in the occlusion groups. In shams, the expression of VEGF and Ang-2 was low and constant at all times. Tie-2 phosphorylation myocardial decreased decreased at day 7 but increased at 21 days of occlusions (P < 0.05). Our results indicate that capillary density was augmented by myocardial ischemia, but after development of collaterals and restoration of flow to the ischemic zone, capillary density returned to control levels. The change in capillary density paralleled with VEGF and Ang-2 expression but was inversely related to Tie-2 phosphorylation. We speculate the coronary angiogenesis is a coordinated event involving the expression of both VEGF and Ang-2 and that therapeutic angiogenic strategies may ultimately require treatment with more than a single factor.