The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections

Abstract

Background: Aortic aneurysms (AA) are pathological dilations of the aorta, associated with an overall mortality rate up to 90% in case of rupture. In addition to dilation, the aortic layers can separate by a tear within the layers, defined as aortic dissections (AD). Vascular smooth muscle cells (vSMC) are the predominant cell type within the aortic wall and dysregulation of vSMC functions contributes to AA and AD development and progression. However, since the exact underlying mechanism is poorly understood, finding potential therapeutic targets for AA and AD is challenging and surgery remains the only treatment option.

Methods: In this review, we summarize current knowledge about vSMC functions within the aortic wall and give an overview of how vSMC functions are altered in AA and AD pathogenesis, organized per anatomical location (abdominal or thoracic aorta).

Results: Important functions of vSMC in healthy or diseased conditions are apoptosis, phenotypic switch, extracellular matrix regeneration and degradation, proliferation and contractility. Stressors within the aortic wall, including inflammatory cell infiltration and (epi)genetic changes, modulate vSMC functions and cause disturbance of processes within vSMC, such as changes in TGF-β signalling and regulatory RNA expression.

Conclusion: This review underscores a central role of vSMC dysfunction in abdominal and thoracic AA and AD development and progression. Further research focused on vSMC dysfunction in the aortic wall is necessary to find potential targets for noninvasive AA and AD treatment options.

Keywords: aortic aneurysm; aortic dissection; pathophysiology; vascular biology; vascular smooth muscle cell.

FIGURE 1

Overview of vSMC functions, stressors influencing vSMC functions and disturbed processes within vSMC during AA and AD development and progression. Apoptosis, phenotypic switch, ECM regeneration and degradation, proliferation and contractility are important functions of vSMC in the aortic wall. Dysregulation of these vSMC functions by infiltrative inflammatory cells and (epi)genetic factors can contribute to AA and AD formation. These pathological conditions activate adaptive responses within vSMC, such as changes in TGF‐β signalling and regulatory RNA expression. Abbreviations: AA, aortic aneurysm; AD, aortic dissection; ECM, extracellular matrix; RNA, ribonucleic acid; TGF‐β, transforming growth factor β; vSMC, vascular smooth muscle cell. Elements were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/; https://creativecommons.org/licenses/by/3.0/

FIGURE 2

Different mechanisms to induce vSMC apoptosis within the aortic wall. Inflammatory cell infiltration into the aortic wall, ischaemic injury, oxidative stress, mechanical wall stress and detachment of the ECM can induce vSMC apoptosis. ER stress and high expression levels of MCP‐1, P53 and BAX proteins within vSMC promote vSMC apoptosis. BCL2, an inhibitor of BAX, is downregulated. Abbreviations and symbols: BAX, Bcl‐2‐associated X protein; BCL2, B‐cell lymphoma 2; ECM, extracellular matrix; ER, endoplasmic reticulum; MCP‐1, monocyte chemoattractant protein‐1; vSMC, vascular smooth muscle cell; ‐ ‐|, inhibitory effect; ↓, Decreased expression; ↑, Increased expression. Elements were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/; https://creativecommons.org/licenses/by/3.0/

FIGURE 3

Vascular smooth muscle cell phenotypic switching. vSMC phenotypic switching can be induced by inflammatory cell infiltration, oxidative stress, mechanical wall stress or vSMC detachment from the ECM caused by ECM degradation. The switch from contractile to synthetic vSMC phenotype results in decreased expression of smooth muscle 22 alpha, alpha smooth muscle actin, smooth muscle myosin heavy chain 2, smoothelin, calponin and vimentin are decreased, while osteopontin is upregulated. Abbreviations and symbols: ECM, extracellular matrix; vSMC, vascular smooth muscle cell; ↓, Decreased expression; ↑, Increased expression. Elements were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/; https://creativecommons.org/licenses/by/3.0/

FIGURE 4

Extracellular matrix degradation by proteolytic enzymes regulated by vSMC. MMP, ADAM and cathepsins, activated and secreted by vSMC, can break down the ECM. Plasminogen can be activated into plasmin by u‐PA or t‐PA, both located on the vSMC membrane. PAI‐1 can inhibit u‐PA, and t‐PA. MMP can be inhibited by TIMP and activated by plasmin. ECM degradation causes vSMC detachment from the ECM and results in vSMC apoptosis, phenotypic switching and reduced contractility. Abbreviations: ADAM, the A disintegrin and metalloproteinase; ECM, extracellular matrix; MMP, matrix metalloprotease; PAI‐1, plasminogen activator inhibitor; TIMP, tissue inhibitors of matrix metalloproteinases; t‐PA, tissue‐type plasminogen activator; u‐PA, urokinase plasminogen activator; vSMC, vascular smooth muscle cell. Elements were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/; https://creativecommons.org/licenses/by/3.0/

FIGURE 5

Inflammatory response in the aortic wall regulated by vSMC and affecting vSMC functions. During AA and AD progression, inflammatory cells infiltrate into the aortic wall. These inflammatory cells, together with vSMC, produce chemokines and interleukins, which subsequently activate various processes in the tunica media. vSMC start producing MMP, in turn causing ECM degradation. vSMC apoptosis is induced and gene expression in vSMC is modulated. In contrast, infiltration of regulatory T cells has a protective effect by inhibiting vSMC apoptosis and ECM degradation. Abbreviations: AA, aortic aneurysm; AD, aortic dissection; ECM, extracellular matrix; MCP‐1, monocyte chemoattractant protein‐1; MMP, matrix metalloprotease; NKT cell, natural killer T cell; vSMC, vascular smooth muscle cell. Elements were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/; https://creativecommons.org/licenses/by/3.0/

FIGURE 6

Overview of the contractile apparatus in vSMC and mutations affecting vSMC functions causing TAAD formation. The contraction of vSMC is initiated by Ca²⁺ influx, binding to calmodulin. This Ca²⁺/Calmodulin complex binds to myosin light chain kinase, which phosphorylates the myosin filaments and results in contraction. Decrease in the Ca²⁺ concentration within in the cell inactivates myosin light chain kinase and de‐phosphorylation of the myosin filaments, controlled by type I cGMP‐dependent protein kinase, results in vSMC relaxation. Mutations in genes encoding for vSMC contractile apparatus proteins (indicated in red) result in reduced force generation. Mutations in genes encoding for the large glycoprotein fibrillin‐1 (indicated in red) affect the structure of microfibrils and result in increased active TGF‐β levels. Mutations in the TGF‐β signalling pathway and downstream proteins (indicated in red) can also contribute to TAAD formation by affecting transcription. Abbreviations: Ca²⁺, calcium ion; P, phosphate; TAAD, thoracic aortic aneurysm and dissection; TGFBR, transforming growth factor β receptor; TGF‐β, transforming growth factor β; vSMC, vascular smooth muscle cell. Elements were modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. https://smart.servier.com/; https://creativecommons.org/licenses/by/3.0/