Aortic regurgitation provokes phenotypic modulation of smooth muscle cells in the normal ascending aorta.

BACKGROUND

Aortic complications are more likely to occur in patients with ascending aortic aneurysms and concomitant aortic regurgitation (AR). AR may have a negative influence on the aortic wall structure even in patients with tricuspid aortic valves and absence of aortic dilatation. It is unknown whether smooth muscle cell (SMC) changes are a feature of AR-associated aortic remodeling.

METHODS

Nondilated aortic samples were harvested intraoperatively from individuals with normal aortic valves (n = 10) or those with either predominant aortic stenosis (AS) (n = 20) or AR (n = 35). Tissue from each patient was processed for immunohistochemistry or used for the extraction of medial SMCs. Tissue and cells were stained for markers of SMC contraction (alpha-smooth muscle actin), synthesis (vimentin) and senescence (p16INK4A and p21Cip1 [p16/p21]). Replicative capacity was analyzed in cultured SMCs from AS- and AR-associated aortas. A subanalysis compared SMCs from individuals with either tricuspid aortic valves or bicuspid aortic valves to evaluate the effect of aortic valve morphology.

RESULTS

In aortic tissue samples, AR was associated with decreased alpha-smooth muscle actin and increased vimentin, p16 and p21 compared with normal aortic valves and AS. In cell culture, SMCs from AR-aortas had decreased alpha-smooth muscle actin and increased vimentin compared with SMCs from AS-aortas. AR-associated SMCs had increased p16 and p21 expression, and they reached senescence earlier than SMCs from AS-aortas. In AR, SMC changes were more pronounced with the presence of a bicuspid aortic valve.

CONCLUSIONS

AR itself negatively influences SMC phenotype in the ascending aortic wall. This AR-specific effect is independent of aortic diameter and aortic valve morphology, although it is more pronounced with bicuspid aortic valves. These findings provide insight into the mechanisms of AR-related aortic remodeling, and they provide a model for studying SMC-specific therapies in culture.