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.

项目概要 强有力的证据表明交感神经系统是外周血管张力的关键调节者 在此，我们提出了神经血管反应的显着性别差异。 缺氧挑战了当前的教条，我们的结果得到了显示性别的流行病学数据的证实。 不同条件下高血压患病率和心血管疾病进展的差异 然而，低氧血症（即睡眠呼吸暂停）的发病机制仍然是一个尚未得到解答的问题。 本研究将填补这一知识空白，同时确定这些机制是否受到损害 近 70% 的美国人口超重或肥胖，其中肥胖率更高。 患有睡眠呼吸暂停的患者表现出更强的交感神经系统活动和更高的风险。 新数据表明肥胖对心血管健康的影响。 女性与男性的比例不成比例，并且有理由认为，通过添加 该应用的目的是检查导致性别差异的关键机制。 在缺氧血管舒张和肥胖的影响中，特别强调对交感神经系统的影响。 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，免受交感神经的影响。 缺氧的血管收缩作用，以及对女性性的“有益”作用随着肥胖而丧失。 初步数据，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 肥胖女性缺氧期间下游一氧化氮介导的血管舒张会减弱，我们将测试我们的结果。 通过以下具体目标实现中心假设：该项目的第一个目标将确定性别差异 急性缺氧期间α-肾上腺素受体介导的血管收缩以及肥胖的影响。 提出了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， 结合正常体重男性肌肉交感神经活动的直接测量，正常体重 该项目的第二个目标将确定直接和调节作用。 我们将收集人体动脉，研究β-肾上腺素受体对缺氧血管舒张以及肥胖的影响。 内皮细胞并测量动脉内注射之前和之后外周血管对缺氧的反应 输注精选的β-肾上腺素能激动剂和拮抗剂，这种实验方法将使我们能够战略性地进行。 评估缺氧和下调情况下 β-肾上腺素能受体的活性、敏感性和表达 我们提出的研究结果将促进对缺氧的基本、机制的理解。 女性的血管控制，结果将最终指导新策略的开发和治疗 预防睡眠呼吸暂停和其他缺氧情况下的血管病理生理学。