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: 10663073
• 负责人: Jacqueline K Limberg
• 金额: $ 53.81万
• 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/10663073
• 关键词: Acute; Adrenergic Agents; Adrenergic Antagonists; Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Adult; Area; Attenuated; Blood Pressure; Blood Vessels; Blood flow; Body mass index; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Chronic; Cohort Studies; Data; Development; Dexmedetomidine; Endothelial Cells; Estrogen Receptor alpha; Estrogens; Exhibits; Exposure to; Failure; Female; Forearm; Functional disorder; Goals; Human; Hypertension; Hypoxemia; Hypoxia; Impairment; Infusion procedures; Intervention; Intra-Arterial Infusions; Isoproterenol; Knowledge; Measures; Mediating; Muscle; Nerve; Neurotransmitters; Nitric Oxide; Norepinephrine; Obesity; Overweight; Oxygen; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Phentolamine; Phenylephrine; Physiological; Plasma; Population; Premenopause; Prevalence; Propranolol; Receptor Activation; Regulation; Relaxation; Research; Resistance; Risk; Risk Factors; Role; Sex Differences; Skeletal Muscle; Sleep Apnea Syndromes; Stress; Sympathetic Nervous System; Testing; Vasoconstrictor Agents; Vasodilation; Weight; Woman; Work; adult obesity; alpha-adrenergic receptor; beta-adrenergic receptor; blood pressure elevation; cardiovascular health; constriction; epidemiologic data; falls; high risk; improved; ineffective therapies; men; mortality; neurovascular; normoxia; novel therapeutics; peripheral blood; pharmacologic; pre-clinical; preservation; prevent; receptor sensitivity; response; sex; sex disparity; vasoconstriction; young man; young woman

PROJECT SUMMARY Strong evidence implicates the sympathetic nervous system as a key regulator of peripheral vascular tone 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 remain 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 during hypoxia 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 the 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 in sleep apnea and other conditions of hypoxia.

项目摘要 有力的证据表明，交感神经系统是周围血管张力和 缺氧期间的血压。本文中，我们在神经血管反应中提出了惊人的性别差异 挑战当前教条的缺氧。我们的结果通过显示性别的流行病学数据来证实 在高血压患病率和心血管疾病进展的差异 低氧血症（即睡眠呼吸暂停）。但是，贡献机制仍然是一个无疑的问题。这 目前的研究将填补这一空白，同时确定这些机制是否受到损害 肥胖。美国近70％的人口超重或肥胖，肥胖症的流行甚至更大 睡眠呼吸暂停的患者。肥胖的成年人表现出更大的交感神经系统活动和更高的风险 高血压比正常体重成年人。新兴数据表明肥胖对心血管健康的影响 在女性与男性中是不成比例的，合理的提议被夸大了 低氧应激。此应用的目的是检查有助于性别差异的关键机制 在低氧血管舒张和肥胖的影响中，特别强调了交感神经系统。 我们的中心假设是年轻的绝经前，正常体重女性受到保护免受同情的保护 缺氧的血管收缩作用以及女性的“有益”作用因肥胖而失去。基于强 初步数据，我们预计α-肾上腺素能介导的血管收缩被夸大，β-肾上腺素能和 肥胖女性缺氧期间，下游一氧化氮介导的血管舒张受到衰减。我们将测试我们的 通过以下特定目的通过以下特定目的假设：该项目的第一个目标将确定性别差异 α-肾上腺素受体介导的急性缺氧期间的血管收缩以及肥胖的影响。我们 提案对α-肾上腺素激动剂和拮抗剂的动脉内药物输注的全面方法， 结合正常体重男性正常体重的直接测量肌肉交感神经活动 妇女和肥胖的妇女。该项目的第二个目的将确定 β-肾上腺素受体对低氧血管舒张以及肥胖的影响。我们将收集人类动脉 内皮细胞并在动脉内和之后测量对缺氧的周围血管反应 输注精选的β-肾上腺素激动剂和拮抗剂。这种实验方法将使我们能够战略性地 评估缺氧和下背景下的β-肾上腺素受体活性，敏感性和表达 流机制。我们提出的发现将提高对低氧的基本机械理解 妇女的血管控制，结果最终将指导制定新的治疗策略 预防睡眠呼吸暂停中的血管病理生理和缺氧其他状况。