Schematic depiction of the main pathways of MF origin, differentiation, and role in vascular remodelling. MFs can derive from resident or circulating precursors under concomitant mechanical and biochemical stimuli. The cytokine TGF-β1 is produced by injured tissue and is the main biochemical inducer of MF differentiation. The TGF-β1 dimer is secreted as part of a larger complex with LAP and LTBP-1. Under ECM stretching or proteolytic cleavage, the TGF-β1 dimer is released and its subsequent binding to the receptor complex TGF-β1RI:TGF-β1RII triggers the intracellular signalling leading to MF maturation, in conjunction with the production of the ED-A isoform of fibronectin through an alternative splicing mechanism. The ED-A Fn can exert a cooperative function with TGF-β1 to activate α-SMA expression in stress fibres of differentiating MFs, whereas proto-MFs contain stress fibres composed of only β- and γ-actins. After tissue repair, MFs can undergo apoptosis or can survive and lead to tissue fibrosis and remodelling, depending on the kind and duration of the injury. Dotted line arrows indicate pathways not yet well established in vivo.
Abbreviations: α-SMA, α-smooth muscle actin; Ang II, angiotensin II; Col I, type I collagen; Col III, type III collagen; ECM, extracellular matrix; ED-A Fn, extradomain type A fibronectin; EMT, endothelial–mesenchymal transition; ET-1, endothelin-1; FAK, focal adhesion kinase; LAP, latency-associated peptide; LTBP-1, latent TGF-β1-binding protein 1; PDGF, platelet-derived growth factor; TGF-β1, transforming growth factor-β1.
There are now clinical, biological, and radiological data establishing that intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) is one of the driving forces of the evolution of dilation toward rupture. ILT is a main source of
1) oxidation, due to the red blood cell (RBC) storage and haem-iron release, and
2) proteolytic activities in AAA, including activation of plasmin and retention of neutrophils, and it is a potential site of weak pathogen contamination.
The pathogenic spatio-temporal role of ILT is directly linked to its permanent renewal at the luminal interface with circulating blood and to the high porosity of this neo-tissue, allowing pressure-dependent outward radial convection of proteases and oxidized molecular mediators towards the arterial wall and the adventitia. Therefore, ILT biology impacts vascular smooth muscle cell disappearance and extracellular matrix degradation in the medial layer of the arterial wall and the angiogenic and adaptive immune responses taking place in the adventitia of AAA.