TGFβ, smooth muscle cells and coronary artery disease: a review

Figures

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  Fig. 1. - Canonical TGFβ signalling pathway. Active TGFβ homodimers signal via binding to specific transmembrane receptor complexes comprised of two type I (TβRI) and two type II (TβRII) serine/threonine kinase receptors. TβRI and TβRII are structurally similar with small cysteine-rich extracellular domains (ECD), single transmembrane domains (TMD) and highly conserved intracellular serine/threonine domains (S/TKD). TGFβ binding to TβRII induces the assembly of TβRII and TβRI receptors into a heteromeric complex, within which constitutively active TβRII phosphorylates TβRI at several serine and threonine residues within its conserved glycine-serine domain (GSD). R-Smads become phosphorylated by the activated TβRI at their C-terminal SSXS motif. The L45 loop of TβRI and the L3 loop of the R-Smad MH2 domain determine R-Smad receptor specificity, with ALK5 specifically phosphorylating Smads 2 and 3. The adaptor protein Smad anchor for receptor activation (SARA) can also facilitate recognition of R-Smads by the receptors. I-Smads contain MH2 domains and can act to turn off Smad TGFβ signalling by interfering with Smad-receptor or Smad-Smad interactions. Phosphorylated R-Smads form a…

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  Fig. 2. – Vascular remodelling during atherosclerosis (A) and after revascularisation surgery (B) (A) Atherosclerosis is initiated by the activation of the endothelium in response to oxidative, haemodynamic or biochemical stimuli. Activated endothelial cells (ECs) upregulate surface adhesion molecules and secrete growth factors and cytokines, promoting rolling adhesion of circulating leukocytes as well as activation of the underlying smooth muscle cells (SMCs). Activated SMCs dedifferentiate and start proliferating and migrating, contributing to the growing neointima. Leukocytes adhering to the endothelium migrate into the intima through diapedesis, maturing into macrophages and phagocytosing low density lipoproteins to become foam cells, characteristic of the ‘fatty streak’ lesions that can be observed from adolescence onwards. Fibroatheromas form from areas of intimal thickening, which consist of foam cells, remnants of apoptotic SMC and a lipid rich ECM pool. Early fibroatheromas are characterised by an acellular necrotic core and a thick fibrous cap, composed of collagen fibrils interspersed with SMCs. Advancing fibroatheromas contain cholesterol crystals, neovessels and lymphocytes,…