Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms

Abstract

Aortic aneurysm, including thoracic aortic aneurysm and abdominal aortic aneurysm, is the second most prevalent aortic disease following atherosclerosis, representing the ninth-leading cause of death globally. Open surgery and endovascular procedures are the major treatments for aortic aneurysm. Typically, thoracic aortic aneurysm has a more robust genetic background than abdominal aortic aneurysm. Abdominal aortic aneurysm shares many features with thoracic aortic aneurysm, including loss of vascular smooth muscle cells (VSMCs), extracellular matrix degradation and inflammation. Although there are limitations to perfectly recapitulating all features of human aortic aneurysm, experimental models provide valuable tools to understand the molecular mechanisms and test novel therapies before human clinical trials. Among the cell types involved in aortic aneurysm development, VSMC dysfunction correlates with loss of aortic wall structural integrity. Here, we discuss the role of VSMCs in aortic aneurysm development. The loss of VSMCs, VSMC phenotypic switching, secretion of inflammatory cytokines, increased matrix metalloproteinase activity, elevated reactive oxygen species, defective autophagy, and increased senescence contribute to aortic aneurysm development. Further studies on aortic aneurysm pathogenesis and elucidation of the underlying signaling pathways are necessary to identify more novel targets for treating this prevalent and clinical impactful disease.

Keywords: aortic aneurysm; genetics; mechanism; vascular smooth muscle cell.

Figure 1. Pathogenesis of aortic aneurysms.

The healthy aorta (left) consists of intimal, medial, and adventitial layers. Vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) maintain integrity of the aortic wall. Aortic aneurysm lesions (right) are characterized by thrombi, infiltration of inflammatory cells (neutrophils, macrophages, B and T cells), degradation of the ECM, VSMC phenotypic switching and apoptosis, excessive production of cytokines, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs). PVAT indicates perivascular adipose tissue.

Figure 2. Comparison of animal models used for aortic aneurysm studies.

Animal models have been developed to recapitulate features of human aortic aneurysms. Aortic aneurysms in rodent species can be induced by several methods, including surgical procedures, pharmacological treatments, and genetic manipulations. Each model has its advantages and drawbacks when comparing with human aortic aneurysm pathology. AAA indicates abdominal aortic aneurysm; AngII, angiotensin II; BAPN, β‐aminopropionitrile; ILT, intraluminal thrombus; IMT, intramural thrombus; MCR, mineralocorticoid receptor; and TAA, thoracic aortic aneurysm.

Figure 3. The role of VSMCs in aortic aneurysms.

VSMCs play a critical role in the development of an aortic aneurysm. In pathological conditions, VSMCs undergo phenotypic switching, cell death (apoptosis and necroptosis), oxidative stress, inflammation, senescence, and insufficient autophagy, contributing to aortic aneurysm development. Critical signaling pathways have been identified to mediate VSMC dysfunction in aortic aneurysms. The schematic illustration also shows the genes/pathways either decreased/inactivated (blue) or increased/activated (red) in aortic aneurysm development. ARHGAP18 indicates Rho GTPase activating protein 18; AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2; ATG5, autophagy related 5; ATG7, autophagy related 7; BCL2, B‐cell lymphoma 2; CCN3, cellular communication network factor 3; ERK1/2, extracellular signal‐regulated kinases 1/2; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; KLF4, Krüppel like factor 4; mTOR, mammalian target of rapamycin; MYOCD, myocardin; NAMPT, nicotinamide phosphoribosyltransferase; NF‐κB, nuclear factor kappa B; NOX4, nicotinamide adenine dinucleotide phosphate oxidase 4; NRF2, nuclear factor erythroid 2‐related factor 2; PPARγ, peroxisome proliferator‐activated receptor‐gamma; RIP1/3, receptor interacting serine/threonine kinase 1/3; SIRT1, sirtuin1; SRF, serum response factor; STAT, signal transducer and activator of transcription; and TFEB, transcription factor EB.