Modulation of coronary collateral angiogenesis: a canine model of neovascularization induced by chronic ischemia

Coronary collateral development in response to chronic myocardial ischemia is modulated by the integrated release of a variety of growth factors. Protamine, a specific inhibitor of angiogenesis in vitro and in vivo, may attenuate coronary collateral development. The purpose of this investigation was to characterize a model of canine coronary collateral development and to ascertain the effects of protamine on collateral perfusion in response to chronic myocardial ischemia. Ischemia-induced coronary collateral enhancement in response to daily, repetitive, 2-minute left anterior descending (LAD) coronary artery occlusions over 22 consecutive days was demonstrated in control (saline treated) dogs by time dependent, significant (p < 0.05) increases in collateral blood flow to ischemic myocardium. Concomitant with increases in collateral perfusion, myocardial contractile function during LAD occlusion was progressively normalized, and percent coronary flow repayment was reduced successively. These indicators of collateral development were attenuated significantly by administration of subcutaneous protamine. The present findings demonstrate that a model of brief, repetitive, coronary artery occlusion in chronically instrumented dogs sensitively elicits extensive enhancement of the coronary collateral circulation in response to chronic myocardial ischemia. In contrast, protamine attenuates coronary collateral development through its actions as an inhibitor of angiogenesis.