Sex disparities in hypoxic sympatholysis and impact of obesity

缺氧交感神经的性别差异和肥胖的影响

• 批准号: 10413582
• 负责人: Jacqueline K Limberg
• 金额: $ 2.42万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413582
• 关键词: Acute; Adrenergic Agents; Adrenergic Antagonists; Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Adult; Attenuated; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Data; Development; Endothelial Cells; Exhibits; Female; Functional disorder; Human; Hypertension; Hypoxemia; Hypoxia; Impairment; Infusion procedures; Intra-Arterial Infusions; Knowledge; Measures; Mediating; Muscle; Nerve; Nitric Oxide; Obesity; Overweight; Oxygen; Patients; Peripheral; Pharmaceutical Preparations; Population; Premenopause; Prevalence; Risk; Sex Differences; Sleep Apnea Syndromes; Stress; Sympathetic Nervous System; Testing; Vasoconstrictor Agents; Vasodilation; Weight; Woman; adult obesity; alpha-adrenergic receptor; base; beta-adrenergic receptor; cardiovascular health; epidemiologic data; high risk; improved; men; neurovascular; novel therapeutics; parent grant; peripheral blood; prevent; response; sex; sex disparity; vasoconstriction

PROJECT SUMMARY Parent grant “Sex disparities in hypoxic sympatholysis and impact of obesity” #R01HL153523 Strong evidence implicates the sympathetic nervous system as a key regulator of peripheral blood flow and blood pressure during hypoxia. Herein, we present striking sex-differences in the neurovascular response to hypoxia that challenge current dogma. Our results are corroborated by epidemiological data showing sex disparities in the prevalence of hypertension and progression of cardiovascular disease in conditions of hypoxemia (i.e., sleep apnea). However, contributing mechanisms (including α- and β-adrenergic receptor activity, sensitivity, and expression) remains a critically unanswered question. The present study will fill this gap in knowledge while also determining whether these mechanisms are impaired with obesity. Nearly 70% of the US population is overweight or obese, with the prevalence of obesity even greater in patients with sleep apnea. Obese adults exhibit greater sympathetic nervous system activity and higher risk for hypertension than normal weight adults. Emerging data indicate the impact of obesity on cardiovascular health is disproportionate in women versus men and it is reasonable to propose this is exaggerated with the addition of hypoxic stress. The purpose of this application is to examine key mechanisms contributing to sex-differences in hypoxic vasodilation and the impact of obesity, with particular emphasis on the sympathetic nervous system. Our central hypothesis is that young premenopausal, normal weight women are protected from the sympathetic vasoconstrictor effects of hypoxia, and the “beneficial” effect of female sex is lost with obesity. Based on strong preliminary data, we anticipate α-adrenergic mediated vasoconstriction is exaggerated and β-adrenergic and downstream nitric oxide-mediated vasodilation are attenuated in obese women. We will test our central hypothesis via the following specific aims: The first aim of this project will determine sex differences in α-adrenergic receptor mediated vasoconstriction during acute hypoxia as well as the impact of obesity. We propose a comprehensive approach of intra-arterial drug infusions of α-adrenergic agonists and antagonists, combined with direct measures of muscle sympathetic nerve activity in normal weight men, normal weight women, and obese women. The second aim of this project will determine the direct and modulatory effect of the β-adrenergic receptors on hypoxic vasodilation as well as impact of obesity. We will collect human arterial endothelial cells and measure the peripheral vascular response to hypoxia prior to and following intra-arterial infusion of select β-adrenergic agonists and antagonists. This experimental approach will allow us to strategically assess β- adrenergic receptor activity, sensitivity, and expression in the context of hypoxia as well as down- stream mechanisms. Our proposed findings will advance the fundamental, mechanistic understanding of hypoxic vascular control in women, and results will ultimately guide the development of new strategies to treat and prevent vascular pathophysiology.

项目摘要 父母资助“缺氧性交感神经溶解的性别差异和肥胖的影响”#R01HL153523 强有力的证据表明，交感神经系统是外周血的关键调节器 缺氧时的血流和血压在此，我们提出了惊人的性别差异， 神经血管对缺氧的反应挑战了当前的教条。我们的结果证实了 流行病学数据显示高血压患病率的性别差异， 在低氧血症条件下心血管疾病的进展（即，睡眠呼吸暂停）。然而，在这方面， 作用机制（包括α和β肾上腺素能受体活性、敏感性和 表达）仍然是一个关键的未回答的问题。本研究将填补这一空白， 同时也确定这些机制是否因肥胖而受损。近 70%的美国人口超重或肥胖， 睡眠呼吸暂停综合征患者肥胖的成年人表现出更大的交感神经系统活动， 高血压的风险高于正常体重的成年人。新出现的数据表明， 肥胖对心血管健康的影响在女性与男性中不成比例， 这一点在缺氧应激的情况下被夸大了。本申请的目的 是研究缺氧性血管舒张的性别差异的关键机制， 肥胖的影响，特别强调对交感神经系统。我们的中央 假设是年轻的绝经前，正常体重的妇女受到保护， 缺氧的交感血管收缩作用，和女性性的“有益”效果是失去了 肥胖症基于强有力的初步数据，我们预期α-肾上腺素能介导的 血管收缩被夸大，β-肾上腺素能和下游一氧化氮介导的 肥胖妇女的血管舒张减弱。我们将通过以下方式检验我们的中心假设 具体目标：本项目的第一个目标是确定α-肾上腺素能受体的性别差异， 急性缺氧时介导的血管收缩以及肥胖的影响。我们提出了一个 α-肾上腺素能激动剂和拮抗剂动脉内药物输注的综合方法， 结合正常体重男性中肌肉交感神经活动的直接测量， 正常体重的女性和肥胖的女性。该项目的第二个目标将确定 β-肾上腺素能受体对缺氧血管舒张的直接和调节作用， 肥胖的影响。我们将收集人动脉内皮细胞并测量外周血 动脉内输注选择性β-肾上腺素能受体激动剂前后血管对缺氧的反应 激动剂和拮抗剂。这种实验方法将使我们能够战略性地评估β- 肾上腺素能受体的活性，敏感性和表达在缺氧的情况下，以及向下- 流机制。我们提出的研究结果将推进基本的， 了解妇女缺氧血管控制，结果将最终指导 开发新的策略来治疗和预防血管病理生理学。