Cardiovascular disease (CVD) is the leading cause of death in the U.S. in both men and women. Although biological sex is an important determinant of CVD pathophysiology, a major knowledge gap remains regarding sex differences in CVD prevention and treatment. A key early event in CVD development is endothelial dysfunction, characterized by impaired flow-mediated dilation (FMD). Aging progressively impairs endothelial function which independently predicts CVD progression and events. Therefore, strategies to optimize endothelial function in aging are clinically important. Regular aerobic exercise ameliorates endothelial dysfunction in healthy older men, but the data in healthy postmenopausal women are inconsistent with many studies showing no effect. The mechanisms underlying these sex disparities are unknown. Higher intensity exercise is thought to be required for chronic endothelial adaptations in postmenopausal women, but this has not been investigated. We have recently developed a novel exercise strategy by adapting high intensity interval training (HIIT) on a non- weight-bearing all-extremity (NWA) ergometer. Our innovative NWA-HIIT can be implemented in a larger portion of the aging population because it allows compensation for lower extremity musculoskeletal problems. The primary objective of this grant application is to examine sex differences in acute and chronic endothelial responses to NWA-HIIT in older men vs. postmenopausal women. Our overarching hypothesis is that acute and chronic endothelial responsiveness to aerobic exercise is influenced by sex in healthy aging and acute endothelial responses to exercise will be predictive of chronic endothelial adaptations. To examine sex differences in chronic exercise adaptations, brachial artery FMD will be determined at baseline, after an 8-week control period and after 8-week NWA-HIIT. To examine sex differences in the acute response to exercise, FMD will be determined at pre-exercise, the end of a single session of NWA-HIIT and after 1-hour and 24-hours post- exercise. The acute responses to NWA-HIIT will be measured in both the untrained and trained state (i.e., at baseline and after 8-week NWA-HIIT). To gain mechanistic insight, we will determine: 1) protein/mRNA levels of key factors in endothelial cells biopsied using a state-of-the-art endovascular technique and peripheral blood mononuclear cells (PBMCs) and 2) circulating factors in blood known to be important for endothelial function. This novel translational application will significantly impact the field by: 1) Addressing a fundamental gap in knowledge regarding how sex influences the impact of acute and chronic aerobic exercise on endothelial function in older adults; 2) Providing preliminary mechanistic insight into sex differences regarding in vivo systemic/cellular/molecular adaptations to exercise in older adults by studying endothelial cells, PBMCs and key factors in blood; and 3) Forming the foundation for future studies focusing on dissecting in vivo the mechanisms underlying sex differences in endothelial adaptations to aerobic exercise.
Biological sex is an important determinant of cardiovascular disease pathophysiology, prevention and treatment. The proposed research will examine sex differences in acute and chronic vascular responses to a novel exercise intervention in older adults. The expected results may have important clinical implications for improving vascular function and preventing cardiovascular disease in both men and women.