Abstract
In this issue, Lee and colleagues, from the laboratory of Drs Ronald Crystal and Todd Rosengart at the New York Hospital-Cornell Medical Center, report their findings on the induction of angiogenesis in the myocardium of pigs by local gene therapy. In carefully analysed and well-controlled experiments, the authors demonstrate that (1) new collateral vessels can be locally and rapidly formed around an occluded circumflex artery without evidence of “steal” from non-ischemic myocardium, by the intramyocardial injection of an adenovirus vector coding for the specific angiogenic protein, VEGF (2) this route of administration yields vector genome localization superior to intracoronary injection and (3) near-normalization of blood flow and myocardial function persists, despite the fact that peak over-expression of VEGF is self-limited. This very important paper provides a sound scientific basis for angiogenic gene therapy of the human heart. It also sets the stage for future experimental and clinical studies which could address questions pertinent to angiogenic therapy of the heart; (1) Is VEGF the optimal angiogenic protein for the induction of new coronary vessels, or should other angiogenic proteins such as angiopoietin-1, hepatocyte growth factor, or leptin be considered? (2) Would the administration of adenovirus vectors coding for two different angiogenic proteins be more or less effective than one? (3) Is there a benefit to angiogenic therapy of the myocardium carried out after the completion of angioplasty or coronary by-pass surgery? (4) Does angiogenic gene therapy of the myocardium generate mainly new capillary vessels, or are small arterial collaterals also induced, and if so, by what mechanism? (5) After neovascularization is induced in the myocardium, how durable must it be to provide significant improvement in cardiac function? and (6) How is neovascularization in an atherosclerotic plaque affected by intramyocardial angiogenic gene therapy? Regarding the latter question, the report by Lee and coworkers is encouraging because it suggests that the type of angiogenic gene therapy which these authors employed may maintain the focality of VEGF and limit the duration of its expression. Therefore, VEGF would not be increased in the systemic circulation and plaque neovascularization would not be exacerbated. Doctors Lee, Crystal, Rosengart and their co-authors are to be commended for this insightful and thoughtful experimental study.
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