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1Departments of Physiology and Anesthesiology, The Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; 2Department of Medicine, Division of Cardiology, Dartmouth Medical School, Hanover, New Hampshire 03755-1404; and 3Department of Physiology and the Center for Cardiovascular Diseases, Louisiana State University Health Sciences Center-New Orleans, New Orleans, Louisiana 70112
Submitted 18 July 2002 ; accepted in final form 4 February 2003
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/mm2, but it decreased to 2,594 ± 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.
coronary collateral; vascular endothelial growth factor; Tie-2
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