Sleep apnea affects up to 20% of the adult population, exposing sufferers to periods of hypoxia/hypercapnia during sleep. Consequences of this condition include significant vascular changes with concomitant hypertension and cardiovascular disease. Sleep apnea patients have elevated circulating endothelin-1 (ET-1) which may contribute to the hypertension and we have previously demonstrated that exposing rats to intermittent hypoxia/hypercapnia (IH/HC) during sleep to mimic sleep apnea causes sustained, ET-1-dependent systemic hypertension. New preliminary data demonstrate that mesenteric resistance arteries from these hypertensive IH rats have augmented vasoconstrictor responses to ET-1 but not to phenylephrine or KCI. Intriguingly, augmented ET-1 constriction in IH/HC arteries appears to be mediated entirely by increases Ca2+ sensitivity while ET constriction in Sham arteries is mediated by increases in both [Ca2+]i and Ca2+ sensitivity. Furthermore, ET-1 appears to activate PKC in IH/HC but not Sham arteries, a pathway shown to increase arterial Ca2+ sensitivity. Therefore, we hypothesize that augmented ET-1-mediated vasoconstriction in arteries from rats made hypertensive with IH/HC is caused by increased activation of PKC signaling.
Three aims will test this hypothesis:
Aim 1) Determine PKC isoform expression, activity and agonist-dependent activation in small mesenteric arteries from Sham and IH/HC treated rats.
Aim 2) Determine the relative contributions of PKC and ROK to ET-1 and PE activation of Ca2+- sensitization in mesenteric arteries from IH/HC and Sham-treated rats.
Aim 3) Determine the effect of IH/HC on basal and agonist stimulated synthesis and degradation of PKC activator, diacylglycerol (DAG) in arteries from Sham and IH/HC rats. Planned studies will determine the role of PKC-dependent Ca-sensitization in augmented ET-1 dependent vasoconstriction in this rat model of sleep apnea. These studies should fundamentally advance our understanding of ET-1 and PKC signaling in vascular smooth muscle and the cardiovascular consequences of chronic exposure to sleep apnea. The anticipated findings are expected to provide a mechanistic explanation for in vivo observations that ET-1 contributes to vascular dysfunction in sleep apnea and other disease states, sometimes when circulating levels of the peptide are not elevated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082799-03
Application #
7667765
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Twery, Michael
Project Start
2007-07-05
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$375,000
Indirect Cost
Name
University of New Mexico
Department
Physiology
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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
Friedman, J K; Nitta, C H; Henderson, K M et al. (2014) Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 increasing endothelin-1 vasoconstrictor reactivity. Vascul Pharmacol 60:17-24
Osmond, Jessica M; Gonzalez Bosc, Laura V; Walker, Benjimen R et al. (2014) Endothelin-1-induced vasoconstriction does not require intracellular Ca²? waves in arteries from rats exposed to intermittent hypoxia. Am J Physiol Heart Circ Physiol 306:H667-73
Jackson-Weaver, Olan; Osmond, Jessica M; Riddle, Melissa A et al. (2013) Hydrogen sulfide dilates rat mesenteric arteries by activating endothelial large-conductance Caýýýýý-activated Kýýý channels and smooth muscle Caýýýýý sparks. Am J Physiol Heart Circ Physiol 304:H1446-54
Webster, Bradley R; Osmond, Jessica M; Paredes, Daniel A et al. (2013) Phosphoinositide-dependent kinase-1 and protein kinase C? contribute to endothelin-1 constriction and elevated blood pressure in intermittent hypoxia. J Pharmacol Exp Ther 344:68-76
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Meyer, Matthias R; Amann, Kerstin; Field, Angela S et al. (2012) Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction. Hypertension 59:507-12
da Silva, Ana Quenia Gomes; Fontes, Marco Antonio Peliky; Kanagy, Nancy Lapp (2011) Chronic infusion of angiotensin receptor antagonists in the hypothalamic paraventricular nucleus prevents hypertension in a rat model of sleep apnea. Brain Res 1368:231-8
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
Jackson-Weaver, Olan; Paredes, Daniel A; Gonzalez Bosc, Laura V et al. (2011) Intermittent hypoxia in rats increases myogenic tone through loss of hydrogen sulfide activation of large-conductance Ca(2+)-activated potassium channels. Circ Res 108:1439-47

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