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 #
1R01HL082799-01A2
Application #
7317316
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Twery, Michael
Project Start
2007-07-05
Project End
2011-06-30
Budget Start
2007-07-05
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
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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