Sex differences in smooth muscle cell behavior in human ascending aortic aneurysms.

Aneurysms originating in the ascending aorta pose a significant risk of mortality and morbidity by exposing patients to the potential of aortic dissection. While numerous studies suggest a higher incidence of ascending thoracic aortic aneurysms (ATAA) in men compared to women, it is noteworthy that complications related to ATAA result in more fatalities among women than men. ATAAs are generally characterized by dysfunction in smooth muscle cells (SMCs) and degradation of the extracellular matrix (ECM). The goal of this project is to identify sex-differentiating factors in SMCs from men and women with ATAA, focusing on SMC dysfunction. Aortic specimens were procured from ATAAs removed during aortic replacement surgeries and from non-aneurysmal (NA) aortas punched for coronary artery bypass grafting or excised during heart transplants conducted at the Brigham and Women’s Hospital. Primary SMCs from both NA and ATAA specimens were isolated via enzymatic digestion, cultured, and expanded. Using a gel compaction assay, we show that SMCs from ATAA specimens exhibit lower contraction than SMCs from non-aneurysmal specimens (NA), but there was no difference between male and female SMCs. However, female SMCs saw their contraction decrease in response to collagen substrates, while the contraction of male SMCs was unaffected. Interestingly, proteomic analyses of aortic specimens revealed that several cytoskeletal proteins involved in SMC contraction exhibit lower expression levels in female ATAA specimens vs. males. Lastly, qPCR analyses showed that growth factors upregulated genes related to mitophagy and antioxidant defense significantly more in SMCs from females ATAA specimens compared to their male counterparts. Collectively, these data show distinct responses to collagen substrates and growth factors in SMCs from male and female ATAA specimens. Subsequent experiments are needed to determine whether these observations contribute to the heightened incidence of aortic complications in women with ATAA compared to men.