In Vitro Investigation of Female-Male Differences under PAD Conditions

Peripheral arterial disease (PAD) is an obstructive condition that commonly affects older populations, with an incidence of 12-20% in those older than 65 yrs. Interestingly, PAD presentation and progression are different in male and females. However, research involving PAD and how biological sex might play a role in this disease is limited. In this study, we used a human aortic endothelial cell (HAEC) in vitro model of PAD characterized by pathological flow and stiffness conditions to analyze the gene expression of HAECs and understand how mechanical stimuli could lead to potential male-female differences in proatherogenic pathways that cause PAD. Furthermore, we have utilized the scRNA-seq tool, which provides comprehensive data related to EC heterogeneity. We found clear male-female differences in the response of human aortic ECs to mechanical stimuli. We validated these findings with a murine model of pathological flow in the carotid arteries. This study not only shows the importance of including biological sex as a study variable when investigating cardiovascular disease, but also opens the door to investigating the molecular pathways that lead to the male-female differences in PAD.