Plaque-associated fibroblasts: Key regulators of atherosclerosis pathogenesis and plaque stability

Gavino Faa; Riccardo Cau; Jasjit S. Suri; Matteo Fraschini; Massimo Castagnola; Luca Saba

doi:10.23750/abm.v96i1.15695

Plaque-associated fibroblasts: Key regulators of atherosclerosis pathogenesis and plaque stability

Authors

Gavino Faa Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
Riccardo Cau Department of Radiology, University of Cagliari, Cagliari, Italy
Jasjit S. Suri Stroke Monitoring and Diagnostic Division, Atheropoint, Roseville, CA, USA
Matteo Fraschini Department of Electric and Electronic Engineering, University of Cagliari, Cagliari, Italy
Massimo Castagnola Laboratory of Proteomics and Metabolomics, IRCCS Santa Lucia Foundation, Rome, Italy
Luca Saba Department of Radiology, University of Cagliari, Cagliari, Italy

Keywords:

atherosclerotic plaque, plaque stability, fibroblast activation, vascular inflammation, extracellular matrix remodeling, atherosclerosis pathogenesis, plaque progression, fibroblasts in cardiovascular disease, vulnerable plaque dynamics

Abstract

This review explores the evolving understanding of the origin and behavior of plaque-associated fibroblasts, with a primary focus on their phenotype and interactions within the plaque microenvironment (PME). These fibroblasts play a crucial role in shaping the plaque's trajectory, either towards stability or instability. The pathological transformation of fibroblasts into myofibroblasts, characterized by increased contractility and secretion, contributes to excessive extracellular matrix (ECM) deposition. Activated myofibroblasts also influence vasa vasorum growth by producing key factors such as vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), and monocyte chemoattractant protein 1 (MCP1).

The bidirectional crosstalk between fibroblasts and inflammatory cells within the plaque is a crucial aspect. Activated fibroblasts release proinflammatory factors like interleukin-1 (IL-1), activating resident immune cells and facilitating their migration through the PME. Conversely, immune cells produce cytokines such as IL-6, TNF-alpha, TGF-beta, and IL-1beta, stimulating fibroblasts to produce matrix metalloproteinase 1 (MMP1) and collagen deposition. The dynamic interplay among these cells, influenced by genetic predispositions, systemic conditions (hypertension, diabetes), inflammatory states (including COVID-19), and environmental factors (diet, lifestyle), determines the plaque's fate. Understanding histological images of atherosclerotic lesions could provide insights for therapeutic strategies aiming to inhibit detrimental smooth muscle cell transitions, promoting plaque stabilization and preventing severe clinical complications arising from carotid atherosclerotic plaque rupture.

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