Project Summary/Abstract The goal of the proposed study is to elucidate mechanisms contributing to the heightened risk of cardiovascular disease (CVD) and hypertension (HTN) in early-menopausal compared to typical-age- menopausal females. The risks of CVD and HTN increase steeply after menopause, but females who complete menopause early (< age 46 yrs.) are more likely to experience HTN and CVD-related morbidity and mortality than those who complete menopause at a typical age (~ 51 yrs.) Furthermore, sympathetic increases in females after menopause, and higher sympathetic drive is associated with cardiovascular mortality and HTN. Postmenopausal females have shown dysregulation in autonomic control of blood pressure (BP), but it is unknown whether BP dysregulation occurs similarly in early-menopausal and typical-age-menopausal females. Moreover, altered vascular transduction, whereby an increase in sympathetic activity causes vasoconstriction, may play a role in the development of HTN. This proposal will investigate sympathetic regulation of blood flow and blood pressure in early- and typical-age-menopausal females. Additionally, individuals who are racialized as non-white have higher cardiovascular risks than white people, and this study will explore perceived discrimination and coping as potential mediators of CVD and HTN in postmenopausal females of diverse backgrounds. To evaluate vascular regulation, forearm vascular conductance (FVC) and muscle sympathetic nerve activity (MSNA) will be measured via venous occlusion plethysmography and microneurography, respectively, in postmenopausal females, ages 50-70 yrs., who completed menopause early or at a typical age. Conductance and MSNA will be measured at rest (SA1) and during a two-minute cold pressor test (CPT) of the hand (SA2). Importantly, BP responses to a CPT can predict future HTN, and greater sympathetic reactivity to a stressor may indicate a higher risk for future CVD. Further, physiological responses and correlations between discrimination and coping scores will be explored (SA3). The hypotheses are that early- menopausal females will have lower resting FVC and higher resting MSNA, and larger changes in FVC and MSNA with CPT, than typical-age-menopausal females; and that higher perceived discrimination and lower coping ability will be associated with higher sympathetic outflow. Dr. Lee will be trained in techniques of microneurography and venous occlusion plethysmography and will engage in career development activities, including grant and scholarship development. In addition, she will be trained in community-engagement strategies during the fellowship duration. She will receive training from an exemplary team in a research-rich environment within the Medical School at the University of Minnesota. This proposal aligns with the NHLBI’s mission, identifying mechanisms contributing to HTN and CVD for development of prevention and treatment strategies to reduce CVD risk in early-menopausal ...