Sex disparities in hypoxic sympatholysis and impact of obesity

项目总结 父母资助：“缺氧性交感神经溶解中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液的关键调节系统 低氧时的血流量和血压。在这里，我们呈现了显著的性别差异 神经血管对缺氧的反应挑战了当前的教条。我们的结果得到了证实 通过流行病学数据显示高血压患病率的性别差异和 在低氧血症(即睡眠呼吸暂停)条件下心血管疾病的进展。然而， 作用机制(包括α和β肾上腺素能受体活性、敏感性和 表达)仍然是一个严重悬而未决的问题。本研究将填补这一空白。 同时还可以确定这些机制是否因肥胖而受损。差一点 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。肥胖的成年人表现出更强的交感神经系统活动， 与正常体重成年人相比，患高血压的风险更高。新出现的数据表明， 肥胖对心血管健康的影响在女性和男性中不成比例，因此有理由 建议这一点由于增加了低氧压力而被夸大了。本应用程序的目的是 是检查导致缺氧性血管扩张的性别差异的关键机制以及 肥胖的影响，特别是对交感神经系统的影响。我们的中央 假设是年轻的绝经前正常体重的女性受到保护，不会受到 低氧的交感血管收缩效应，而女性的“有益”效应就消失了 与肥胖有关。基于强大的初步数据，我们预计α-肾上腺素能介导 血管收缩被夸大，β-肾上腺素能及下游一氧化氮介导 肥胖女性的血管扩张功能减弱。我们将通过以下方式测试我们的中心假设 具体目标：该项目的第一个目标将确定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 动脉内注射α-肾上腺素能激动剂和拮抗剂的综合方法， 结合对正常体重男性肌肉交感神经活动的直接测量， 体重正常的女性和肥胖的女性。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细胞 动脉内输注选择性β-肾上腺素能前后血管对缺氧的反应 激动剂和拮抗剂。这一实验方法将使我们能够战略性地评估β- 肾上腺素能受体在低氧和低氧环境中的活性、敏感性和表达 流机制。我们提出的发现将推进根本的、机械性的 对女性低氧血管控制的了解和结果最终将指导 开发治疗和预防血管病理生理学的新策略。

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.