miRNA Regulation of Cell Phenotype and Parietal Remodeling in Atherosclerotic and Non-Atherosclerotic Aortic Aneurysms: Differences and Similarities

Abstract

Aortic aneurysms are a serious health concern as their rupture leads to high morbidity and mortality. Abdominal aortic aneurysms (AAAs) and thoracic aortic aneurysms (TAAs) exhibit differences and similarities in their pathophysiological and pathogenetic features. AAA is a multifactorial disease, mainly associated with atherosclerosis, characterized by a relevant inflammatory response and calcification. TAA is rarely associated with atherosclerosis and in some cases is associated with genetic mutations such as Marfan syndrome (MFS) and bicuspid aortic valve (BAV). MFS-related and non-genetic or sporadic TAA share aortic degeneration with endothelial-to-mesenchymal transition (End-Mt) and fibrosis, whereas in BAV TAA, aortic degeneration with calcification prevails. microRNA (miRNAs) contribute to the regulation of aneurysmatic aortic remodeling. miRNAs are a class of non-coding RNAs, which post-transcriptionally regulate gene expression. In this review, we report the involvement of deregulated miRNAs in the different aortic remodeling characterizing AAAs and TAAs. In AAA, miRNA deregulation appears to be involved in parietal inflammatory response, smooth muscle cell (SMC) apoptosis and aortic wall calcification. In sporadic and MFS-related TAA, miRNA deregulation promotes End-Mt, SMC myofibroblastic phenotypic switching and fibrosis with glycosaminoglycan accumulation. In BAV TAA, miRNA deregulation sustains aortic calcification. Those differences may support the development of more personalized therapeutic approaches.

Keywords: Marfan syndrome; abdominal aortic aneurysm; atherosclerosis; bicuspid aortic valve; calcification; endothelial dysfunction; fibrosis; miRNA deregulation; smooth muscle cell dedifferentiation; thoracic aortic aneurysm.

Figure 1

Schematic representation of miRNA deregulation-related pathogenic mechanisms in atherosclerotic abdominal aortic aneurysms. Atherosclerotic process prevails in the progression of abdominal aortic aneurysm (AAA) and is characterized at least in part by miRNA deregulation-driven endothelial dysfunction, inflammation, smooth muscle cell (SMC) proliferation, migration and apoptosis, fibroatheromatous plaque formation and thrombosis, with medial fibrosis and calcification (insert, Hematoxylin and Eosin staining).

Figure 2

Schematic representation of miRNA deregulation-related pathogenic mechanisms in thoracic aortic aneurysms. Thoracic aortic aneurysms (TAAs) are sporadic or frequently related to genetic diseases. Sporadic and Marfan syndrome disease (MFS) TAAs show an aortic cell differentiative process, in which endothelial cells switch into a mesenchymal phenotype, whereas medial SMCs switch into a myofibroblastic phenotype and synthetize collagen and glycosaminoglycan with consequent aortic degeneration and fibrosis (inserts (a,b), Masson’s Trichrome Goldner staining). Those processes are precocious, much more marked and strongly accentuated in MFS TAAs, in which TGF-β signaling is hyperactivated. Genetic bicuspid aortic valve (BAV) TAA displays a specific degenerative process, in which SMCs dedifferentiate into osteoblast-like cells promoting medial calcification (insert (c), Alizarin Red staining) by miRNA deregulation-mediated activation of NOTCH and BMP signaling.