Matsunaga Toshiro, Warltier David C, Tessmer John, Weihrauch Dorothee, Simons Michael, Chilian William M
Department of Physiology and Anesthesiology, The Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H352-8. doi: 10.1152/ajpheart.00621.2002. Epub 2003 Mar 20.
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 2378 +/- 53 (sham) to 2962 +/- 60/mm2, but it decreased to 2594 +/- 39/mm2 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.
缺血后冠状动脉毛细血管生长的潜在机制尚不清楚。我们推测血管内皮生长因子（VEGF）和血管生成素（Ang）/Tie-2的表达参与了毛细血管生长，作为对缺血的一种适应性反应。为了验证这一假设，我们在长期植入仪器的犬类动物中，测量了反复心肌缺血发作期间的毛细血管密度，以及VEGF、Ang-1、Ang-2、Tie-2受体的表达及其磷酸化状态。通过多次（每小时1次；每天8次）短暂（2分钟）阻断左前降支冠状动脉1、7、14或21天来诱导反复缺血发作。假手术组接受与实验组相同的仪器植入，但不进行阻断操作。侧支血流（微球法）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2378±53（假手术组）增加到2962±60/mm2，但在第21天降至2594±39/mm2。心肌间质液中VEGF和Ang-2的表达（Western分析）在反复阻断的第3天达到峰值，但随后下降。相比之下，阻断组中Ang-1的表达在所有时间都保持相对恒定。在假手术组中，VEGF和Ang-2的表达始终较低且恒定。Tie-2磷酸化在阻断第7天时心肌中降低，但在第21天时增加（P<0.05）。我们的结果表明，心肌缺血增加了毛细血管密度，但在侧支循环形成和缺血区血流恢复后，毛细血管密度恢复到对照水平。毛细血管密度的变化与VEGF和Ang-2的表达平行，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涉及VEGF和Ang-2表达的协调事件，治疗性血管生成策略最终可能需要用多种因子进行治疗。
