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

Abstract

AbstractBackgroundAortic complications are more likely to occur in patients with ascending aortic aneurysms and concomitant aortic regurgitation (AR). AR may have a negative impact 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.MethodsNon-dilated aortic samples were harvested intra-operatively 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; ASMA), synthesis (vimentin) and senescence (p16/p21). Replicative capacity was analyzed in cultured SMCs from AS- and AR-associated aortas. A sub-analysis compared SMCs from individuals with either TAVs or BAVs to rule out the effect of aortic valve morphology.ResultsIn aortic tissue samples, AR was associated with decreased ASMA and increased vimentin, p16 and p21 compared to normal aortic valves and AS. In cell culture, SMCs from AR-aortas had decreased ASMA and increased vimentin compared to 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 BAV.ConclusionsAR itself negatively impacts SMC phenotype in the ascending aortic wall, which is independent of aortic diameter and aortic valve morphology. These findings provide insight into the mechanisms of AR-related aortic remodeling, and they provide a model for studying SMC-specific therapies in culture.