The Pathophysiological Role of Vascular Smooth Muscle Cells in Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is the most common aortic disease occurring below the renal arteries, caused by multiple etiologies. Currently, no effective drug treatment exists, and the specific pathogenesis remains unclear. Due to its insidious onset and diagnostic challenges, AAA often culminates in aortic rupture, which has a high mortality rate. During AAA development, vascular smooth muscle cells (VSMCs) undergo significant pathological alterations, including contractile dysfunction, phenotypic modulation, cellular degradation, and heightened inflammatory and oxidative stress responses. In particular, emerging evidence implicates vascular smooth muscle cell (VSMC) metabolic dysregulation and mitochondrial dysfunction as key contributors to AAA progression. In this review, we systematically summarize the current understanding of VSMC biology, including their developmental origins, structural characteristics, and functional roles in aortic wall homeostasis, along with the regulatory networks governing the VSMC phenotype and functional maintenance. This review highlights the urgent need for further investigation into the aortic wall VSMC pathophysiology to identify novel therapeutic targets for AAA. These insights may pave the way for innovative treatment strategies in aortic disease management.

Keywords: abdominal aortic aneurysm; aortic lesion; pathophysiology; vascular biology; vascular smooth muscle cells.

Figure 1

Characteristic changes in the aortic wall during the development of AAA. In the normal aorta (left), the vessel wall comprises three layers: the intima, media, and adventitia. Among these, VSMCs and the ECM within the medial layer are essential for maintaining the structural integrity, elasticity, and tensile strength of the aortic wall. When elastic fibers in the media are markedly reduced and VSMCs are lost or undergo apoptosis, the abdominal aorta loses mechanical support, resulting in pathological dilation and the formation of an AAA (right). During this pathological process, inflammatory mediators are released in a cascade, triggering and promoting the recruitment of inflammatory cells. Mitochondrial metabolic dysfunction and ROS activation within VSMCs contribute to impaired contractility. In addition, increased levels of MMPs facilitate ECM degradation, while cytokines and pro-apoptotic factors accelerate VSMC phenotypic switching, degradation, and apoptosis. Abbreviations: VSMCs: vascular smooth muscle cells; AAA: abdominal aortic aneurysm; MMPs: matrix metalloproteinases; ECM: extracellular matrix; ROS: reactive oxygen species.

Figure 2

Embryonic origins of vascular smooth muscle cells in the aorta. This schematic illustrates the developmental processes of vasculogenesis and angiogenesis, highlighting the stepwise formation and maturation of the vascular system. Endothelial cells (ECs) originate from mesodermal progenitors and assemble into a primitive vascular plexus. Subsequently, smooth muscle cells (SMCs) and pericytes are recruited to stabilize and mature the vasculature. The aortic regions are color-coded, with an emphasis on the abdominal aorta (yellow), which derives its vascular smooth muscle primarily from paraxial mesoderm and lateral plate mesoderm, as indicated. This regional origin contrasts with the neural crest-derived SMCs of the ascending aorta and aortic arch, underscoring the spatial heterogeneity in vascular development. Abbreviations: SMCs: smooth muscle cells; ECs: endothelial cells.

Figure 3

The mechanism by which inflammatory cells and their secreted cytokines (TNF-α, IL-1β, IL-6, MCP-1, and IFN-γ) affect VSMCs during the development of AAA. Inflammatory cells release cytokines that induce phenotypic transformation of normal VSMCs—from a contractile phenotype characterized by the expression of α-SMA and SM22α to a synthetic or even inflammatory phenotype. Inflammatory VSMCs produce MMPs, chemokines, and adhesion molecules, which further exacerbate local inflammation. At the same time, cytokines promote VSMC death (including apoptosis and necrosis induced by reactive oxygen species, ROS), and the contents released by dying cells contribute to ECM degradation, particularly through MMP-2 and MMP-9. This ultimately leads to structural destruction of the arterial wall and the formation and progression of AAA. Overall, the diagram reflects a pathogenic feedback loop between inflammation and VSMCs. Abbreviations: AAA: abdominal aortic aneurysm; VSMCs: vascular smooth muscle cells; MMPs: matrix metalloproteinases; ECM: extracellular matrix; ROS: reactive oxygen species.

Figure 4

Illustration of VSMC contractile-synthetic switching during AAA progression. VSMCs exhibit high plasticity and can switch between two phenotypes to adapt to environmental changes. The differentiated VSMCs are in a “quiescent” state, expressing high levels of contractile proteins that enable stable smooth muscle contraction. Key markers of this phenotype include SMMHC, α-SMA, SM22, CNN1, and SMTN. The synthetic VSMCs, on the other hand, express low levels of contractile proteins but have high levels of molecules associated with proliferation, migration, fibrosis, and inflammation, such as OPN, EREG, KLF4, and BMP2. VSMCs may undergo transdifferentiation during disease progression or upon external stimulation, becoming more unstable phenotypic cells. Abbreviations: AAA: abdominal aortic aneurysm; VSMCs: vascular smooth muscle cells.

Figure 5

Molecular mechanisms of vascular smooth muscle cell phenotype switching during aneurysm formation. The phenotype switching of VSMCs is regulated by various cytokines and signaling pathways. Cytokines such as Ang II, PDGF-BB, TGF-β, and TGF-α can activate signaling pathways, including Notch, ERK/MAPK, PI3K/Akt, JAK/STAT, and TGF-β/Smad, which mediate intracellular ROS activation, inflammation, and endoplasmic reticulum stress, ultimately promoting phenotype switching. Abbreviations: VSMCs: vascular smooth muscle cells; TGF-β: transforming growth factor beta; ROS: reactive oxygen species; TGF-β: transforming growth factor beta; PDGF-BB: platelet-derived growth factor-BB; TNF-α: tumor necrosis factor alpha; ERK1/2: extracellular signal-regulated kinase 1/2; Ang II: angiotensin II; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; JAK: Janus kinase Janus; STAT: signal transducer and activator of transcription.