Myocardial hypertrophy is associated with progressive contractile dysfunction, increased vulnerability to ischemia/reperfusion injury, and is, therefore, a well-recognized risk factor in cardiac surgery. During the progression of myocardial hypertrophy, a mismatch develops between the number of capillaries per unit area and cardiomyocytes, indicating an increase in diffusion distance between cardiomyocytes and vessels. Hypertrophying cardiomyocytes are likely exposed to a limited supply of oxygen and nutrients. Treating hypertrophied hearts with vascular endothelial growth factor (VEGF), enhanced capillary growth, improved tolerance to ischemia and preserved myocardial contractile function. Based on this observation, we hypothesize that in pressure-overload hypertrophy, despite the multitude of adaptive changes that occur in myocytes, there is no significant adaptive response in the capillary endothelial or non-myocyte cells, but the response to exogenous growth factors is preserved. In a model of left ventricular pressure-overload hypertrophy in immature rabbits, we will investigate whether an increase in diffusion distance between capillaries and hypertrophying myocytes results in relative myocyte hypoxia with stimulation of the hypoxia-induced signaling pathway or in an impairment of nutrient substrates. We will then evaluate therapeutic strategies aimed at promoting angiogenesis and targeting matrix turnover, complementing pro-angiogenic treatment in hypertrophied myocardium. We propose to pursue three specific aims:
Aim 1 - Determine whether regulation of hypoxia inducible factor-1 (HIF-1) activity and its downstream effectors such as VEGF is altered in hypertrophied myocardium;
Aim 2 - Determine the effects of pro-angiogenic exogenous growth factors on the microvasculature of the hypertrophying myocardium;
Aim 3 - Determine the effect of pro-angiogenic therapy on matrix remodeling in hypertrophying myocardium and the role of specific matrix metalloproteinases (MMP). Improved understanding of the primary mechanisms involved in response of the myocardium to chronic pressure overload may facilitate the development of new therapeutic modalities to prevent and/or delay the onset of failure. The applicant is dedicated to pursue an academic career concentrating on topics relevant to pediatric cardiac surgery. The five-year time frame provided by this grant will serve as a transitional period between postdoctoral training and independent faculty position.
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