Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in AAA formation and reflects the importance of SMCs plasticity in AAA formation. Although evidence from the wide variety of mouse models is convincing, how this knowledge is applied to human biology needs to be addressed urgently leveraging modern in vitro and in vivo experimental technology.

Keywords: DNA methylation; abdominal aortic aneurysm; epigenetics; extracellular matrix; histone acetylation; lncRNA; miRNA; phenotypic switching; single nucleotide polymorphism; vascular smooth muscle cells.

Figure 1

Schematic of the abdominal aortic aneurysm (AAA) aorta and vascular cells involved in the degradation of the extracellular matrix (ECM). Vascular smooth muscle cells (VSMCs), endothelial cells (EC), and macrophages (Mɸ) release cytokines that elevate inflammation in AAA and promote VSMC proliferation as well as apoptosis. VSMCs, macrophages, and fibroblasts also contribute to the elevation of matrix metallopeptidases (MMPs), which lead to ECM degradation. miR-712 targets tissue inhibitor of metallopeptidase (TIMP)3 to further promote ECM degradation in AAA. Downregulation of miR-24 and miR-143 lead to increased inflammation.

Figure 2

Schematic depicting regulators of histone acetylation and DNA methylation in AAA. Histone deacetylases (HDAC) and histone acetylase transferases (HAT) provide post-transcriptional modification via removing or attaching an acetyl group at the lysine residue. HDAC inhibitors (HDACi) MS-275, MC1568, and metacept (MCT) inhibit acetylation, which has been shown to reduce levels of matrix metallopeptidases (MMP)-2 and-9, and in turn protect the extracellular matrix from degradation. The SET and MYND domain-containing (SMYD) promoter region is hypomethylated in AAA compared to controls. SMYD itself is able to methylation of promoters of interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and hypoxia inducible factor 1 α (HIF1α) and suppress inflammatory signaling.

Figure 3

Schematic depicting the genetic and epigenetic mechanisms that are involved in the phenotypic modulation of smooth muscle cells (SMCs) in AAA. Single nucleotide polymorphisms in selected genes including cyclin dependent kinase 2B antisense (CDKN2BAS/ANRIL), DAB2IP, lipoprotein receptor-related protein 1 (LRP1), and receptor-interacting serine/threonine-protein kinase 3 (RIPK3) have been shown to be associated with the diseased SMC phenotype as depicted by increased proliferation that leads to vascular remodeling, inflammation, and cell death. miR-24 selectively targets Chi311 to inhibit proliferation. Kruppel-like factor 4 (KLF4) normally represses myocardin to downregulate SMC differentiation and promote the synthetic phenotype. miR-145 can repress KLF4 and, in turn, inhibit de-differentiation into the synthetic SMC phenotype. miR-146a, miR-261, and mir-221/222 have been reported to promote SMC proliferation.