Endothelial SK3 Channel Modulation of EDHF is Estrogen Regulated

描述(申请人提供)：包括更年期和卵巢切除在内的生理变化会导致心血管系统不可逆的变化，这些变化往往会导致血管张力的内皮依赖性调节减弱，并可能导致高血压。血管内皮细胞中的钙信号是许多内皮衍生血管活性因子的关键调节因子，包括内皮素、前列腺素、一氧化氮和内皮衍生超极化因子(EDHF)。几种K+通道在血管内皮细胞中表达，它们对钙信号的作用不同，这在很大程度上是由于它们特有的生物物理特性和亚细胞定位。最近的工作表明，SK3(小电导钙激活的K+，亚型3)通道在EDHF介导的血管松弛中起关键作用，影响血管张力和血压。该方案的目的是确定SK3通道调节血管张力的细胞和分子机制，以及雌激素如何调节SK3通道活性和EDHF诱导的血管扩张。John Adelman博士是国际公认的SK渠道研究科学家，他将提供主要的指导指导，并由一个共同指导和顾问团队补充，以反映OHSU社区的优势。高血压，即所谓的“沉默杀手”，是一个深刻而广泛的健康问题，也是可能进一步导致心血管疾病发病率和死亡率的主要风险因素，而心血管疾病是发达国家的头号死因。了解血管内皮细胞SK3通道的功能、表达、分布和调控，可能会为高血压及其后遗症的治疗提供新的治疗策略，改善大量人群的生活质量。) 公共卫生相关性：心血管疾病是美国的主要死亡原因。绝经后、衰老和高血压都是心血管疾病发病率和死亡率的主要危险因素。年龄匹配的男性通常比绝经前的女性患心血管疾病的风险更大；然而，绝经后的女性失去了心脏保护。这一建议旨在检验雌激素调节内皮钾通道以调节血管反应性和血压的假设。)

DESCRIPTION (provided by applicant): Physiological changes including menopause and ovariectomy induce irreversible changes in the cardiovascular system that frequently result in diminished endothelium-dependent regulation of vascular tone and can lead to hypertension. Ca2+ signaling in vascular endothelium is a key regulator for many of the endothelium-derived vasoactive factors, including endothelins, prostaglandins, nitric oxide, and endothelium- derived hyperpolarizing factor (EDHF). Several K+ channels are expressed in vascular endothelium that contribute differently to Ca2+ signaling due in large part to their characteristic biophysical properties and sub- cellular localizations. Recent work demonstrates that SK3 (small-conductance Ca2+-activated K+, subtype 3) channels play a crucial role in EDHF-mediated vasorelaxation, influencing vascular tone and blood pressure. The goal of this proposal is to determine the cellular and molecular mechanisms through which SK3 channels regulate vascular tone, and how estrogen modulates SK3 channel activity and EDHF-induced vasodilation. Dr. John Adelman is an internationally recognized scientist in SK channel research and will provide primary mentoring guidance that will be complemented by a team of co-mentors and consultants, reflecting the strengths of the OHSU community. Hypertension, the so-called "silent killer", is a profound and widespread health issue, and is a major risk factor that can further lead to cardiovascular morbidity and mortality, the number one cause of death in developed countries. Understanding endothelial SK3 channel function, expression, distribution, and regulation may reveal novel therapeutic strategies for the treatment against hypertension and its deleterious sequelae, improving the quality of life for a significant population. ) PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death in the United States. Post-menopause, aging, and hypertension are all major risk factors of cardiovascular disease morbidity and mortality. Age-matched men are generally at greater risk than premenopausal women for cardiovascular disease; however, after menopause women lose their cardioprotection. This proposal is designed to test the hypothesis that estrogen regulates endothelial potassium channels to modulate vascular reactivity and blood pressure.)