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: 10202732
• 负责人: Jacqueline K Limberg
• 金额: $ 49.12万
• 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/10202732
• 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; Pharmacology; 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; base; beta-adrenergic receptor; cardiovascular health; epidemiologic data; falls; high risk; improved; ineffective therapies; men; mortality; neurovascular; normoxia; novel therapeutics; peripheral blood; 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.

项目总结 强有力的证据表明，交感神经系统是周围血管张力和 低氧时的血压。在这里，我们提出了显著的性别差异的神经血管反应 挑战当前教条的缺氧症。我们的结果得到了流行病学数据的证实 高血压患病率和心血管疾病进展在以下条件下的差异 低氧血症(即睡眠呼吸暂停)。然而，贡献机制仍然是一个严重悬而未决的问题。这个 目前的研究将填补这一知识空白，同时也将确定这些机制是否受到损害 肥胖。近70%的美国人口超重或肥胖，肥胖症的患病率在 患有睡眠呼吸暂停的患者。肥胖成年人表现出更强的交感神经系统活动和更高的患病风险 高血压比正常体重的成年人要高。新数据显示肥胖对心血管健康的影响 在女性和男性中是不成比例的，有理由认为这一点被夸大了，因为增加了 低氧应激。这个应用程序的目的是检查导致性别差异的关键机制。 在低氧血管扩张和肥胖的影响下，特别强调交感神经系统。 我们的中心假设是，年轻的绝经前、体重正常的女性受到保护，不会受到交感神经的影响 低氧的血管收缩作用，而女性性行为的“有益”作用随着肥胖而消失。基于强大的 初步数据显示，我们预计α-肾上腺素能介导的血管收缩被夸大，而β-肾上腺素能和 肥胖女性缺氧时，下游一氧化氮介导的血管扩张功能减弱。我们将测试我们的 中心假设通过以下具体目标：该项目的第一个目标将确定性别差异 α-肾上腺素能受体介导的急性缺氧时的血管收缩以及肥胖的影响。我们 提出一种动脉内注入α-肾上腺素能激动剂和拮抗剂的综合方法， 结合肌交感神经活动在正常体重男性中的直接测量 女性和肥胖女性。该项目的第二个目标将决定 β-肾上腺素能受体对缺氧性血管扩张以及肥胖的影响。我们将收集人体动脉 并测量动脉插管前后外周血管对低氧的反应 输注精选的β肾上腺素能激动剂和拮抗剂。这种实验性的方法将使我们能够从战略上 评估β-肾上腺素能受体在低氧和低氧环境下的活性、敏感性和表达 流机制。我们提出的发现将促进对缺氧的基本的、机械性的理解 女性的血管控制，结果将最终指导新的治疗和治疗策略的发展 防止睡眠呼吸暂停等条件下的血管病理生理缺氧。