Smooth Muscle Heterogeneity and Plasticity in Health and Aortic Aneurysmal Disease

Abstract

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching to contribute to the deteriorating aortic wall structure. Recently, the unprecedented heterogeneity and diversity of VSMCs and their complex relationship to aortic aneurysms (AAs) have been revealed by high-resolution research methods, such as lineage tracing and single-cell RNA sequencing. The aortic wall consists of VSMCs from different embryonic origins that respond unevenly to genetic defects that directly or indirectly regulate VSMC contractile phenotype. This difference predisposes to hereditary AAs in the aortic root and ascending aorta. Several VSMC phenotypes with different functions, for example, secreting VSMCs, proliferative VSMCs, mesenchymal stem cell-like VSMCs, immune-related VSMCs, proinflammatory VSMCs, senescent VSMCs, and stressed VSMCs are identified in non-hereditary AAs. The transformation of VSMCs into different phenotypes is an adaptive response to deleterious stimuli but can also trigger pathological remodeling that exacerbates the pathogenesis and development of AAs. This review is intended to contribute to the understanding of VSMC diversity in health and aneurysmal diseases. Papers that give an update on VSMC phenotype diversity in health and aneurysmal disease are summarized and recent insights on the role of VSMCs in AAs are discussed.

Keywords: VSMC; abdominal aortic aneurysm; phenotypic switching; thoracic aortic aneurysm.

Figure 1

VSMC phenotypic diversity in hereditary AAs. The aortic wall consists of VSMCs from different embryonic origins that respond unevenly to genetic defects that directly or indirectly regulate VSMC contractile phenotype, which results in heterogeneous susceptibility to aortic diseases. (A) provides an overview of the origin of VSMCs in the aortic wall. The ascending aorta is composed of VSMCs derived from SHF and CNC. The former wraps outside of the latter in a “sleeve-shaped” form, However, mesoderm-derived VSMCs predominate in the abdominal aorta. (B) depicts a plausible hypothesis that the ascending aorta is susceptible to AAs and ADs when genetic defects are present. VSMCs with distinct embryonic backgrounds show different responses to signaling perturbations. Compared to CNC-derived VSMCs, SHF-derived VSMCs are more prone to lose their contractile phenotype and cause pathological ECM remodeling. This leads to a reduction in the strength of the aortic wall, making it susceptible to swelling. Moreover, the turbulent blood flow can easily cause tearing along the interface between the 2 VSMCs, leading to the occurrence of ADs in the presence of damaged endothelium. (C) shows the dysfunctional phenotypes of VSMCs from different origins with genetic defects. Fibrillin-1 is the primary protein found in the microfibril extensions of elastic lamellae, which are attached to focal adhesions on the surface of VSMCs. It is also associated with TGF-β binding proteins (LTBP), which are involved in the TGF-β signaling pathway. Genetic defects in fibrillin-1 (MFS) and defects in the TGF-β signaling pathway (LDS) affect the phenotype of both VSMCs, with SHF-derived VSMCs being more susceptible to loss of the contractile phenotype. The direction of arrows indicates the trend of gene expression levels: upward represent upregulation, horizontal indicate stable expression levels, and downward indicate downregulation. Vascular smooth muscle cells, VSMCs; Secondary heart field, SHF; Cardiac neural crest, CNC; Extracellular matrix, ECM; Aortic aneurysms, AAs; Aortic dissections, ADs; Loeys-Dietz syndrome, LDS; Marfan syndrome, MFS.

Figure 2

VSMC phenotypic diversity in non-hereditary AAs. VSMCs transform into different phenotypes and show a high degree of plasticity when exposed to detrimental stimuli. In the thoracic aorta, secreting VSMCs cause deposition of ECM components. Proliferative VSMCs undergo active proliferation and immune-related VSMCs will exert immune clearance and immunomodulatory effects. In the long term, these non-contractile phenotypes can result in pathological remodeling and, ultimately, to TAAs. In the abdominal aorta, stressed VSMCs are standing at the at the crossroads of necrosis/apoptosis or compensation. Pro-inflammatory VSMCs maintain and exacerbate vessel wall inflammation, eventually exhausting proliferative VSMCs and triggering a senescent phenotype, which leads to VSMC depletion and disruption of aortic wall integrity, triggering AAAs. Arrows indicates the gene expression changes: the number of arrows indicates the magnitude of expression change, and the direction of arrows indicates the trend, upward represent upregulation, horizontal indicate stable expression levels, and downward indicate downregulation1.