Perfluorooctane sulfonate aggravates intimal hyperplasia and atherosclerosis by promoting phenotypic switching of smooth muscle cells via ERK/tPA pathway.

Perfluorooctane sulfonate (PFOS), a pervasive environmental contaminant, is ubiquitously detected in water, air, soil, and food chains. Emerging evidence has implicated PFOS in the pathogenesis of cardiovascular diseases, particularly atherosclerosis - the fundamental pathological process underlying diverse cardiovascular and cerebrovascular disorders. A previous study demonstrated that PFOS exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice through pro-inflammatory M1 macrophage polarization. However, the effects of PFOS on vascular smooth muscle cells (VSMCs) and their contribution to intimal hyperplasia and atherosclerosis remain unexplored. Our in vitro investigations revealed that PFOS potentiates proliferation, migration, and phenotypic switching in primary human aortic smooth muscle cells (HASMCs). Moreover, we also demonstrated that PFOS exposure aggravated neointimal formation in a femoral artery injury model and promoted atherosclerosis. To elucidate the role of VSMCs in these processes in vivo, we established a VSMCs lineage-tracing model utilizing Myh11-Cre/ERT2; R26-tdTomato; ApoE-/- mice. Following 16 weeks of PFOS exposure, atherosclerotic plaque progression exhibited a positive correlation with intraplaque VSMCs accumulation. RNA sequencing analysis and subsequent validation confirmed PFOS-induced tissue plasminogen activator (tPA) upregulation in VSMCs at both transcriptional and translational levels. Notably, tPA knockdown abrogated PFOS-driven proliferation, migration, and phenotypic switching in HASMCs. Mechanistic studies revealed ERK signaling pathway activation as the primary mediator of PFOS-induced tPA expression. Collectively, these findings provide novel mechanistic insights into how PFOS aggravates intimal hyperplasia and atherosclerosis, highlighting its role in exacerbating cardiovascular pathogenesis. They further suggest that ERK inhibitors may mitigate the detrimental effects of PFOS on the vasculature.