From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta

Abstract

Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.

Figure 1

Common features and specificities of TAA vs. AAA.

Figure 2

vSMC involvement in TAA pathogenesis and subsequent responses.

Figure 3

Neutral albumin staining (in blue) in the luminal media of healthy aorta vs. TAA.

Figure 4

Different impacts of vSMC tensegrity on the main molecular components of TAA and AAD pathophysiology (ECM, TGF-β canonical pathway, SMC cytoskeletton and nucleoskeletton: (A) physiological tensegrity involving intracellular components and interactions within SMC, and ECM submitted to cyclic hemodynamic stretching; (B) impact of SMC relaxation on tensegrity and consequences. The behaviour of TGF-β in this context remains to be defined (?); (C) Defect in ECM (enzymatic, genetic, and pharmacologic) released active TGF-β; (D) Progressive dilation increases stretching and induces chromatin remodelling via tensegrity-induced cyto/nucleoskeletton more interactions.

Figure 5

Schematic representation of the pathophysiological determinants of TAA and AAD and the central role of vSMCs.