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

Background and objective: Plaque-associated fibroblasts (PAFs) 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. 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 plaque microenvironment (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. This review discusses the natural progression of carotid plaque and the evolving concepts surrounding the multiple events underlying vulnerable atherosclerotic lesions. Method: Google Scholar, Scopus, and PubMed were searched for manuscripts on PAFs and those reporting the association between PAFs and atherosclero-sis. Conclusion: Advances in our interpretation of histological images of atherosclerotic lesions may pave the way for novel therapeutic strategies aimed at inhibiting detrimental PAF activity, thereby facilitating further plaque stabilization and preventing severe clinical complications arising from carotid atherosclerotic plaque rupture. (www.actabiomedica.it).