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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058124-04
Application #
6537315
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Gail, Dorothy
Project Start
1999-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2002
Total Cost
$262,705
Indirect Cost
Name
University of New Mexico
Department
Physiology
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Zhang, Bojun; Naik, Jay S; Jernigan, Nikki L et al. (2018) Reduced membrane cholesterol after chronic hypoxia limits Orai1-mediated pulmonary endothelial Ca2+ entry. Am J Physiol Heart Circ Physiol 314:H359-H369
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
Norton, Charles E; Jernigan, Nikki L; Kanagy, Nancy L et al. (2011) Intermittent hypoxia augments pulmonary vascular smooth muscle reactivity to NO: regulation by reactive oxygen species. J Appl Physiol (1985) 111:980-8
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
Bosc, Laura V González; Resta, Thomas; Walker, Benjimen et al. (2010) Mechanisms of intermittent hypoxia induced hypertension. J Cell Mol Med 14:3-17
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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