Recent studies suggest that chronic exposure to hypoxia causes upregulation of both endothelial and inducible nitric oxide synthase (eNOS and iNOS, respectively) within the lung. Responses to endothelium-derived NO (EDNO)-dependent dilators are enhanced the arterial vasculature of the lung under hypoxic conditions. However, the mechanisms by which eNOS and iNOS gene expression are increased in hypoxia-induced pulmonary hypertension are unclear. The two most likely possibilities are: 1) a direct effect of hypoxia on gene expression; or 2) an effect of altered mechanical forces secondary to pulmonary hypertension. In regulation of pulmonary NO and endothelin biosynthesis under these clinically relevant conditions.
The specific aims are:
Specific Aim 1 - Determine whether hypoxia per se or pulmonary hypertension is responsible for altered vasoreactivity and upregulation of eNOS and iNOS in lungs from chronically hypoxic rats;
Specific Aim 2 - Determine whether pulmonary hypertension in the absence of hypoxia alters pulmonary vascular reactivity and expression of eNOS and iNOS;
Specific Aim 3 - Determine the roles of increased shear stress, hypoxia and endothelin on eNOS and iNOS expression in cultured cells and in isolated arteries;
and Specific Aim 4 - Examine the potential in vivo interactions between the endothelin and NOS systems in hypoxia-induced pulmonary hypertension. The proposed experiments utilize a variety of in vivo and in vitro approaches to examine questions central to the regulation of the pulmonary circulation under clinically relevant conditions.
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