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1 Department of Physiology and Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Physiology and Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology and Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: chilian{at}lsuhsc.edu.
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/Tie2 were involved in capillary growth as an adaptation to ischemia. To test this hypothesis we measured capillary density, and the expressions of VEGF, angiopoietin-1 and 2 (Ang-1 and Ang-2, respectively) and the Tie-2 receptor and its phosphorylation state (pY-Tie2) during repetitive episodes of myocardial ischemia in chronically instrumented canines. Repetitive episodes of ishemia were induced by multiple (once/hour; 8/day), brief (2 minutes) occlusions of the LAD 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/100 g 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. Tie2 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 Tie2 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.
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