What mechanisms underlie coronary collateral growth?

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The purpose of this grant is to define the role of endogenous stem cells in coronary collateral growth. This problem is significant because patients with ischemic heart disease, who have well developed collaterals show a lower incidence of sudden death, have smaller infarcts in the event of an occlusion, and demonstrate a better prognosis than patients with poorly developed collaterals. Currently, there is no evidence (pro or con) that endogenous stem cells are even involved in coronary collateral growth. One goal of the present application is to rectify this deficiency by establishing if stem cells participate in coronary collateral growth and then the mechanisms underlying this effect. Within this context we propose three aims. In the first aim, we will determine the factors produced by the myocardium and coronary vasculature that induce homing and reprogramming of bone marrow stem cells. In this aim, we will define which factors that are produced by the heart and/or growing vasculature activate stem cell homing to the heart and coronary collateral vasculature. Studies will be performed to examine gain and loss of function of 4 key factors to establish their roles in this adaptive, important process. We also will determine if these factors also induce reprogramming of bone marrow in addition to their effects of homing. Reprogramming is used in this context to suggest that these factors will increase the population of sub-classes of bone marrow cells that are committed to a vascular differentiation program. In the second aim, we will determine if stem cells that are recruited to the heart or to the growing vasculature are essential for the process of collateral growth. We will first establish the sub-types of stem cells that home to the heart and coronary vasculature. Then will we study if depletion or enrichment of these cells (during the creation of the chimeric model) will blunt or magnify, respectively, coronary collateral growth. After we have established the type of stem cells that are critical for coronary collateral growth, our studies will focus on the third aim to delineate the fate of the stem cells in the heart by addressing the question: Do they engraft in collateral arteries and differentiate into smooth muscle or endothelium? The overarching goal of these studies is to fill the current void in our understanding about the role of endogenous stem cells in the growth of coronary collaterals. If coronary collateral growth could be stimulated it would theoretically obviate the need for a bypass as a collateral is “nature’s bypass.” Our overall approach is to use the experience of diverse research team in many disciplines—physiology, vascular biology, in vivo imaging, biochemistry, molecular biology—to address this problem.