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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| Paffett, Michael L; Naik, Jay S; Riddle, Melissa A et al. (2011) Altered membrane lipid domains limit pulmonary endothelial calcium entry following chronic hypoxia. Am J Physiol Heart Circ Physiol 301:H1331-40 |
| Riddle, Melissa A; Hughes, Jennifer M; Walker, Benjimen R (2011) Role of caveolin-1 in endothelial BKCa channel regulation of vasoreactivity. Am J Physiol Cell Physiol 301:C1404-14 |
| Snow, Jessica B; Gonzalez Bosc, Laura V; Kanagy, Nancy L et al. (2011) Role for PKC? in enhanced endothelin-1-induced pulmonary vasoconstrictor reactivity following intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol 301:L745-54 |
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| Bosc, Laura V González; Resta, Thomas; Walker, Benjimen et al. (2010) Mechanisms of intermittent hypoxia induced hypertension. J Cell Mol Med 14:3-17 |
| Paffett, Michael L; Riddle, Melissa A; Kanagy, Nancy L et al. (2010) Altered protein kinase C regulation of pulmonary endothelial store- and receptor-operated Ca2+ entry after chronic hypoxia. J Pharmacol Exp Ther 334:753-60 |
| Broughton, Brad R S; Jernigan, Nikki L; Norton, Charles E et al. (2010) Chronic hypoxia augments depolarization-induced Ca2+ sensitization in pulmonary vascular smooth muscle through superoxide-dependent stimulation of RhoA. Am J Physiol Lung Cell Mol Physiol 298:L232-42 |
| Jernigan, Nikki L; Paffett, Michael L; Walker, Benjimen R et al. (2009) ASIC1 contributes to pulmonary vascular smooth muscle store-operated Ca(2+) entry. Am J Physiol Lung Cell Mol Physiol 297:L271-85 |
| Snow, Jessica B; Kanagy, Nancy L; Walker, Benjimen R et al. (2009) Rat strain differences in pulmonary artery smooth muscle Ca(2+) entry following chronic hypoxia. Microcirculation 16:603-14 |
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