This proposal requests funds to investigate the microvascular adaptations that serve to maintain oxygen transport during increased oxygen demands and decreased oxygen supply (ambient hypoxia). My long-term objectives are in demonstrating what factors regulate capillary growth and the extent to which capillary growth may be a part of the adaptations important for survival under conditions of hypoxia. Some diseases in almost every branch of medicine are dominated by abnormal capillary growth. Thus, understanding the relationships between capillarity and exchange is of paramount importance in determining the effects of stress or pathologies on exchange, and the extent to which capillary growth may serve to offset a particular stress or, in fact, may be a part of the stress. Surprisingly, however, what factors act directly on vessels in the micro-circulation to insure that capillarity is appropriately matched to tissue requirements and what factors stimulate capillary growth in response to changes in supply or demands are still only poorly understood. The specific hypothesis to be tested is that capillary growth is an important adaptive response to increased oxygens demands and decreased oxygen supply. However, capillarity is only one part of a suite of mechanisms involved with the exchange of gases between blood and cell. The entire suite of adaptations accounts for exchange and the critical measure of this exchange is diffusive conductance. In the present work we will: l) quantify the parameters that determine diffusive conductances including (a) erythrocyte volume in capillary blood, capillary surface area and c) diffusion distances; 2) determine the importance of capillarity relative to the other parameters in determining diffusive conductance; 3) determine the extent to which capillary growth is an adaptive response to altered oxygen demands and altered oxygen supply in context with the other parameters that may modify diffusive conductance. In addition, we will determine the extent to which normal maturation alters the potential for modifying diffusive conductance via changes in capillarity. The proposed research will provide a comprehensive view of the relationships between capillarity and tissue oxygenation and the extent to which capillary growth may be a mechanism for altering rates of tissue oxygenation.
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