Previous work from this laboratory strongly suggests that collateral growth is initiated by a hypoxic stimulus, but that mechanical influences also play a role in vascular development. The proposed studies are aimed at and represent a continuation of our efforts to investigate pathophysiological conditions under which myocardial vascular changes occur in an attempt to elucidate the underlying mechanisms leading to vascular growth. To this end, we propose to 1) study whether in high altitudes acclimatized dogs, which experience hypobaric hypoxia and reduced coronary blood flow velocity, the hypoxic stimulus leads to vascular growth. (In contrast to chronic anemia which exhibits both a hypoxic stimulus and increased coronary blood flow.); 2) determine whether an elevated pressure, in the presence of ischemia, can promote collateral (our studies show that hypertension, per se, does not promote collateral growth; 3) explore whether an increased blood flow velocity, in the absence of hypoxia and at a normal hematocrit, acts as a stimulus for coronary vascular growth; 4) quantitate the distribution and functional significance of intramyocardial collaterals in the normal dog and pig heart; and 5) determine whether intramyocardial collateral growth is stimulated for the same conditions that influence epicardial collateral proliferation. We have shown anatomical evidence for the existence of intramyocardial collaterals as they course through the subendocardium. Furthermore, we have shown that these collaterals can supply up to one half of the total collateral flow. Thus, this circulation can be potentially important in limiting damage to the most vulnerable portion of the heart, the subendocardium. In recent studies we noted biventricular hypertrophy and decreased perfusion/g myocardium with renovascular hypertension and aortic banding. However, with chronic severe anemia we have seen a dissociation between hypertrophy and decreased myocardial vascularity. Investigations regarding myocardial hypertrophy and vascularity shall remain a secondary aspect of the above studies. Vascular adaptations to all interventions will take place in a conscious intact animal. At the endpoint of the studies, an isolated heart preparation will be used to quantitate changes in the coronary and collateral vasculature. Insight into these processes will elucidate some of the underlying mechanisms for vascular growth ultimately suggesting ways to reduce ischemic injury in men.
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