Hyperoxia is known to differentially regulate vascular tone contingent on the vascular bed involved. For example, hypoxia causes systemic vasodilation yet initially causes acute pulmonary vasoconstriction, and if sustained leads to profound remodeling of the pulmonary vasculature culminating in structural-based increases in pulmonary vascular resistance and in pulmonary hypertension. The molecular mechanisms underlying the differential vascular responses to hypoxia remain largely unknown. However, recent studies have demonstrated that hypoxia- inducible genes including endothelin-1, platelet-derived growth factor, vascular endothelial growth factor, and inducible nitric oxide synthase play important roles in the vascular cells' adaptive response to hypoxia. The applicant's laboratory has observed that hypoxic stress can result in marked induction of the stress inducible gene heme oxygenase-1 (HO-1) in systemic aortic vascular smooth muscle cells (aVSM) but not in pulmonary vascular smooth muscle cells (pVSM). The molecular basis by which hypoxia differentially regulates HO-1 expression in a VSM and pVSM is not known. Interestingly, carbon monoxide (CO), a major catalytic by-product of HO activity, is a gaseous molecule which can activate guanylyl cyclase and stimulate cGMP production, regulate vascular tone via vasodilatory effects and modulate gene expression, similar to the effects of nitric oxide. The functional role of HO-1 induction and thus CO in the vascular response to hypoxic stress is also poorly understood. Against this background, the applicants hypothesize that the differential expression of HO-1 in systemic and pulmonary vascular cells is mediated by distinct transcriptional regulation and that the HO-1 induction play an important role in mediating the lung's adaptive response to hypoxia. They will test their hypothesis by addressing the following SPECIFIC AIMS: (1) Determine the differential molecular regulation of HO-1 gene activation between hypoxic pulmonary vascular smooth muscle (pVSM) and aortic vascular smooth muscle (aVSM) cells. (2) Determine the differential molecular regulation of HO-1 gene activation between hypoxic pulmonary endothelial (pEC) and aortic endothelial (aEC) cells. (3) Determine the functional role of HO-1 and CO in vitro after hypoxia using the inducible tetracycline regulated expression system. (4) Determine the functional role of HO-1 and CO in vivo after hypoxia using genetically altered mice.
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