Intramuscular injection of AAV vectors is an efficient way of delivering secretory proteins such as erythropoietin and Factor IX. It appears, therefore, that this vector could be useful for delivering angiogenic factors for the treatment of coronary heart disease. Preliminary experiments indicate that this model of administration may indeed by useful. VEGF delivered by AAV vectors into the myocardium by intracardiac injection was compared in mice with or without coronary artery ligation. In mice with ligated coronary arteries, ne blood vessel formation was seen, whereas in the mice with intact coronary, very few blood vessels were seen. (1) The first aim of this project is to extend these studies to a larger number of animals. Because the pathophysiological changes associated with ligation of the coronary artery are much better established in rats, these studies will be performed on rats. The animals will be examined by electrophysiology and echocardiography before they are sacrificed for histological examination for pathology and blood vessel formation. Also, a new method for three dimensional imaging of cardiac blood vessels will be used. (2) A second aim of this project is to investigate methods of regulating angiogenic factors of expression in the myocardium. As it has been shown that high level of expression of VEGF in the myocardium may result in hemangioma formation, it is important to control the expression of angiogenic factors. The first may result in hemangioma formation, it is important to control the expression of angiogenic factors. The first mode of regulation that we will investigate that we will investigate is to use the hypoxia responsive element from the erythropoietin gene. Preliminary data showed several copies of this element arranged in tandem could increase the expression of genes in response to anoxia. Other inducible promoters such as the tetracycline or the progesterone receptor system will be tested. (3) A third aim is to improve the quality and quantity of new blood vessel formation. The angiopoietin and fibroblast growth factor, alone and in combination with VEGF will be investigated.
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