Over the last seven years we have developed a pig model of chronic ischemia which offers an opportunity to study mechanisms of collateral development, sustained exercise induced ischemia and adaptation of the chronically ischemic myocardium. From these observations we now hypothesize that (1) the effect of pharmacologic interventions on coronary collateral development depends on the stage of development in which the intervention occurs; (2) the effect of angiogenic growth factors on coronary collateral development can be modified by blocking the inflammatory response associated with ischemic injury to the myocardium; and (3) coronary microvascular endothelial cells subjected to hypoxia have altered growth characteristics, mitogen responses and leukocyte adhesion responses which also modify collateral growth. In this revised renewal our specific aims have been modified to address these hypotheses.
Our specific aims i n this proposed research are: (1) to determine if pharmacologic interventions will increase the rate of collateral development and collateral reserve. These interventions will be studied in the early (0-5 weeks) and late (5-10 weeks) stages of development. The interventions will include heparin and dobutamine (alone and in combination), SKF TL94424-4, nicotinamide and triiodothyronine (T-3); (2) to characterize the morphometry of the vasculature in the bed at risk as angiogenesis and remodeling occurs; (3) to block the effects of angiogenic growth factors derived from macrophages and platelets during the inflammatory response to coronary artery occlusion; (4) to characterize the growth and mitogen responses of endothelial cells derived from coronary microvasculature and aortas of pigs and from atrial coronary microvasculature and umbilical veins of humans (HUVEC) and to investigate the cell biology of leukocyte adherence molecules on human atrial coronary microvascular endothelial cells, compared to the known standard of HUVEC; (5) to study the occurrence and cell biology of porcine equivalents to the human leukocyte adhesion molecules, i.e. ELAM, ICAM-1, ICAM-2 and GMP-140, in porcine endothelial cell (PEC) cultures derived from aortae and coronary microvessels of the pig. These studies will focus on the in vitro response of PEC to hypoxia, the requirement for new protein or RNA synthesis and the influence of leukocyte-derived cytokines on the relative expression of the adhesion molecules. These studies will examine the roles of the 4 adhesion molecules in the generation of the inflammatory response which promotes collateral growth in the early stages of myocardial ischemia; (6) to determine the gene expression of angiogenic growth factors (bFGF, aFGF, PDGF and TGF) at the cellular level by in situ cDNA:mRNA hybridization in models of coronary collateral development in the pig.
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