Senescence and Inflamm-Aging Are Associated With Endothelial Dysfunction in Men But Not Women With Atherosclerosis

Coronary artery disease (CAD) is a major cause of death worldwide, and more prevalent in men than in women. This study examines explored the differences in endothelium-dependent relaxation and associated transcriptomic signature in plaque-free internal thoracic arterial segments of age-matched men and women undergoing CABG procedure. Endothelium-dependent relaxations were better in female arteries compared to male. Using single nuclei mRNA sequencing, our analysis revealed the prevalence of senescence-associated inflammation in male but not female endothelial cells (EC), that also had longer telomeres than male EC. Furthermore, we found a large common transcriptomic signature in EC of men with severe endothelial dysfunction and in EC expressing CDKN1A (p21), a canonical marker of cellular senescence, validating the link between senescence, inflammation and endothelial dysfunction in men. In contrast, compared to male, female EC overexpressed pathways suggestive of a better stress resistance in association with the better endothelial function. Nuclei were isolated from internal thoracic arteries from 12 patients with coronary artery disease (CAD) undergoing an in-patient CABG, including 6 men and 6 women