Endothelial SK3 Channel Modulation of EDHF is Estrogen Regulated

描述（由申请方提供）：生理变化（包括绝经和卵巢切除术）可诱导心血管系统发生不可逆变化，经常导致血管张力的内皮依赖性调节减弱，并可导致高血压。血管内皮中的Ca 2+信号传导是许多内皮源性血管活性因子的关键调节因子，所述内皮源性血管活性因子包括内皮素、胰高血糖素、一氧化氮和内皮源性超极化因子（EDHF）。几种K+通道在血管内皮中表达，其对Ca 2+信号传导的贡献不同，这在很大程度上是由于其特征性生物物理性质和亚细胞定位。最近的研究表明，SK 3（小电导Ca 2+激活的K+，亚型3）通道在EDHF介导的血管舒张中起着至关重要的作用，影响血管张力和血压。本提案的目标是确定SK 3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SK 3通道活性和EDHF诱导的血管舒张。John Adelman博士是SK渠道研究领域国际公认的科学家，他将提供主要的指导，并将由一个共同导师和顾问团队进行补充，反映OHSU社区的优势。高血压，即所谓的“无声杀手”，是一个深刻和广泛的健康问题，是一个主要的风险因素，可进一步导致心血管疾病发病率和死亡率，这是发达国家的头号死亡原因。了解内皮SK 3通道的功能，表达，分布和调节可能会揭示新的治疗策略，用于治疗高血压及其有害后遗症，改善生活质量的显着人群。) 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、老龄化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。与绝经前女性相比，绝经后匹配的男性患心血管疾病的风险更大;然而，绝经后女性失去了对心脏的保护。该提案旨在验证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.)