Chronic hypoxia (CH) results from pulmonary disorders such as COPD and from residence at high altitude. CH elicits a variety of responses within the cardiovascular system. In contrast to the pulmonary vasculature where long-term hypoxemia is associated with hypertension, the systemic circulation demonstrates a persistent generalized reduction in vasoconstrictor reactivity. This latter phenomenon accounts for the observation that patients suffering from hypoxemic disorders display significant systemic vasodilation that may impair acute regulation of blood pressure. The present proposal will investigate the hypothesis that altered vascular reactivity following CH is due to enhanced endothelial activity of the enzyme heme oxygenase with resultant increased production of carbon monoxide (CO). CO, in turn, activates endothelial BK channels to cause hyperpolarization leading to vasodilation. We also will test the hypothesis that the activities of heme oxygenase and endothelial BK channels are enhanced following CH by their dissociation from the scaffolding protein caveolin-1. There are three hypothesis-driven aims for the project: 1) Test the hypothesis that activity of endothelial BK channels promotes vasodilation following chronic hypoxia. Experiments proposed in this aim will examine the functional role of endothelial BK channels in both vasodilatory responses and in offsetting vasoconstriction in arteries from CH rats. Completion of this aim will establish a role of endothelial BK channels in the previously observed effect of CH to promote vasodilation. 2) Test the hypothesis that endothelial cell BK channel activity is enhanced following chronic hypoxia by dissociation of the channel from caveolin-1. Recent data suggest that endothelial BK channels are associated with caveolin-1 which acts to limit their activity. Experiments in this aim will examine the significance of association of endothelial BK channels with caveolin-1 in intact arteries on channel activity and determine if CH affects this relationship. Completion of this aim will provide novel information on how the association of endothelial BK channels with caveolin-1 affects vasoreactivity and how hypoxia alters this interaction. 3) Test the hypothesis that endothelial HO and BK channels are functionally coupled following CH.
This aim will determine if endothelial HO activity is increased following CH by dissociation from caveolin-1 and if HO and BK channels act as a regulatory unit controlling endothelial cell membrane potential and vascular reactivity. Completion of this aim will establish the presence of a novel mode of vascular regulation present following CH. Together, the proposed studies will provide mechanistic insight to explain the previously observed effect of CH to diminish vasoconstrictor reactivity. These experiments will also generate important information on a potentially novel mechanism of local vascular regulation involving endothelial HO and BK channels. Although the current design investigates the role of CH to unmask this pathway, it is likely that these results could be extended in the future to other pathophysiological conditions where endothelial caveolae are similarly affected.
This project investigates the mechanisms that account for altered control of blood pressure in a model that mimics pulmonary diseases such as chronic obstructive pulmonary disease, chronic bronchitis as well as residence at high altitude where oxygenation is impaired. In these settings, maintenance of blood pressure may be compromised. This research project explores a novel theory to explain this phenomenon.
|Jackson-Weaver, Olan; Osmond, Jessica M; Naik, Jay S et al. (2015) Intermittent hypoxia in rats reduces activation of Ca2+ sparks in mesenteric arteries. Am J Physiol Heart Circ Physiol 309:H1915-22|
|Plomaritas, Danielle R; Herbert, Lindsay M; Yellowhair, Tracylyn R et al. (2014) Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 307:L419-30|
|Nitta, Carlos H; Osmond, David A; Herbert, Lindsay M et al. (2014) Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 306:H41-52|
|Osmond, Jessica M; Gonzalez Bosc, Laura V; Walker, Benjimen R et al. (2014) Endothelin-1-induced vasoconstriction does not require intracellular CaÂ²âº waves in arteries from rats exposed to intermittent hypoxia. Am J Physiol Heart Circ Physiol 306:H667-73|
|Norton, Charles E; Broughton, Brad R S; Jernigan, Nikki L et al. (2013) Enhanced depolarization-induced pulmonary vasoconstriction following chronic hypoxia requires EGFR-dependent activation of NAD(P)H oxidase 2. Antioxid Redox Signal 18:1777-88|
|Jackson-Weaver, Olan; Osmond, Jessica M; Riddle, Melissa A et al. (2013) Hydrogen sulfide dilates rat mesenteric arteries by activating endothelial large-conductance CaÃ½Ã½Ã½Ã½Ã½-activated KÃ½Ã½Ã½ channels and smooth muscle CaÃ½Ã½Ã½Ã½Ã½ sparks. Am J Physiol Heart Circ Physiol 304:H1446-54|
|Riddle, Melissa A; Walker, Benjimen R (2012) Regulation of endothelial BK channels by heme oxygenase-derived carbon monoxide and caveolin-1. Am J Physiol Cell Physiol 303:C92-C101|
|Sweazea, Karen L; Walker, Benjimen R (2012) Impaired myogenic tone in mesenteric arteries from overweight rats. Nutr Metab (Lond) 9:18|
|Jernigan, Nikki L; Herbert, Lindsay M; Walker, Benjimen R et al. (2012) Chronic hypoxia upregulates pulmonary arterial ASIC1: a novel mechanism of enhanced store-operated Ca2+ entry and receptor-dependent vasoconstriction. Am J Physiol Cell Physiol 302:C931-40|
|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|
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