It is estimated that up to 20% of American adults suffer from sleep apnea with an increased risk of developing hypertension and vascular dysfunction. We have observed that simulating sleep apnea in rats by exposing them to intermittent hypoxia (IH) during sleep also increases blood pressure, augments constrictor sensitivity and impairs endothelial dilation. These vascular changes appear to be due in part to loss of the synthesis of the vasodilator, hydrogen sulfide (H2S). Proposed studies will evaluate the mechanisms of H2S- induced vasodilation and determine how IH exposure impairs H2S signaling to impair vasodilation. H2S is a recently described vasodilator produced in the vasculature by cystathionine gamma-lyase (CSE). H2S hyperpolarizes and relaxes vascular smooth muscle cells (VSMC) but much is still unknown about where, when and how it acts. Genetic deletion of CSE in mice elevates blood pressure and impairs endothelium- dependent dilation supporting its role as an important regulator of the vasculature. Our recent studies reveal that H2S causes vasodilation by activating large-conductance calcium-sensitive potassium channels (BKCa) in endothelial cells, eBK. This autocrine effect of H2S has not previously been investigated and is the focus of this proposal. CSE expression in EC is regulated by the transcription factor, NFATc3 and our data suggest IH decreases NFATc3 activation in EC leading to decreased CSE expression and impaired H2S- induced dilation. Our long term goal is to define H2S signaling in the vascular wall, to understand its regulation during intermittent hypoxia and to clarify its role in normal and pathological vascular function. The guiding hypothesis for the proposed studies that H2S activates eBK to mediate dilation and that IH disrupts this pathway by decreasing CSE expression.
The first Aim of the project is to evaluate H2S activation of K+ channels in endothelial cells.
The second Aim i s to define the mechanism IH-induced decreases in CSE-dependent vasodilation expression.
The third Aim i s to Evaluate H2S regulation of blood flow in renal, mesenteric and hindquarters vascular beds determine how IH alters the regulation to contribute to elevated blood pressure. Together the proposed studies will define H2S signaling at molecular, tissue and whole animal levels to increase our understanding of how H2S contributes to cardiovascular control. Defining the causes of dysregulated H2S signaling in IH-exposed rats will also provide a rational basis for the future development of therapies targeting to effectively treat hypertension and peripheral vascular disease in the sleep apnea population.
It is estimated that up to 20% of the American adult population suffers from sleep apnea and that one third suffer from peripheral vascular disease. Both conditions increase the risk for renal failure, myocardial infarction, cardiac ischemia and death from cardiovascular causes. This study uses laboratory rats to investigate basic vascular control mechanisms that appear to be deranged in many vascular disease states including sleep apnea and which appear to contribute to increased vascular disease in rats with simulated sleep apnea. The proposed studies examine potential mechanisms causing vascular disease in this model of sleep apnea and investigate prospective pharmacological interventions to prevent or reverse vascular disease caused by sleep apnea and other forms of hypertension.
| Gonzalez Bosc, Laura V; Osmond, Jessica M; Giermakowska, Wieslawa K et al. (2017) NFAT regulation of cystathionine ?-lyase expression in endothelial cells is impaired in rats exposed to intermittent hypoxia. Am J Physiol Heart Circ Physiol 312:H791-H799 |
| Kanagy, Nancy L; Szabo, Csaba; Papapetropoulos, Andreas (2017) Vascular biology of hydrogen sulfide. Am J Physiol Cell Physiol 312:C537-C549 |
| Naik, Jay S; Osmond, Jessica M; Walker, Benjimen R et al. (2016) Hydrogen sulfide-induced vasodilation mediated by endothelial TRPV4 channels. Am J Physiol Heart Circ Physiol 311:H1437-H1444 |
| 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 |
| Osmond, Jessica M; Kanagy, Nancy L (2014) Modulation of hydrogen sulfide by vascular hypoxia. Hypoxia (Auckl) 2:117-126 |
