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 pathop...