This proposal is directed to study the effect of systematic hypoxia on vascular endothelial function. The technique of intravital microscopy will be used to observe the microcirculation of intact, relatively undisturbed rats, exposed to different levels of inspired PO2. While the endothelial response to ischemia/reperfusion has been studied extensively, the effects of systematic hypoxia such as altitude exposure and acute and chronic pulmonary disease. Our preliminary studies indicate that hypoxia induced by breathing 10% O2 results in increased leukocyte-endothelial interaction in both mesentery and skeletal muscle venules within a few minutes of the onset of hypoxia, followed by leukocyte extravasation. In spite of what appears to be a generalized, severe endothelial injury, rats acclimatized for 3 weeks to comparable levels of hypoxia than that which promotes endothelial dysfunction in non-acclimatized rats, suggesting an acclimatization of the microcirculation.
The specific aims of this proposal are: 1. To determine the mechanisms responsible for the early response to hypoxia: this will include further characterization of the initial vascular endothelial response; identification of the possible mediators of this phenomenon, including reactive oxygen species, nitric oxide and lipid inflammatory mediators; and identification of the leukocyte-endothelial adhesion molecules involved in this response. 2. To evaluate the potential mechanisms involve din the acclimatization of endothelial vascular function to prolonged hypoxia: this will include studies of the role played by factors such as reactive O2 species, up-regulation of inducible nitric oxide synthase, heme oxygenase-1 and vascular endothelial growth factor, as well as the possible role in this process of the improved tissue oxygenation that results from acclimatization. These studies will address a poorly understood subject and should provide significant new information on the mechanisms utilized by intact organisms to respond to systemic hypoxia.
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