Chronic Disturbed Flow Induces Superficial Erosion-Prone Lesion via Endothelial-to-Mesenchymal Transition in a DNA Methyltransferase-Dependent Manner

Aim: Superficial erosion accounts for approximately one-third of all cases of acute coronary syndrome (ACS). Previously, we found that a nearby bifurcation is independently associated with superficial erosion; however, the effect of long-term oscillatory flow on superficial erosion remains unexplored. Endothelial-to-mesenchymal transition (EndMT) is a dynamic process in which endothelial cells acquire mesenchymal properties and, in turn, give rise to smooth muscle cell (SMC)-like cells and extracellular matrix (ECM) accumulation, similar to the autopsy pathology of superficial erosion. This finding prompted us to suspect that EndMT plays a role in the effect of chronic oscillatory flow on superficial erosion.

Methods: We established oscillatory flow in mouse carotid arteries and analyzed neointimal hyperplasia, endothelial continuity, ECM content, and EndMT markers 4 weeks later. Furthermore, bioinformatic data analyses and in vitro studies were performed to elucidate the underlying mechanisms.

Results: Carotid arteries exposed to long-term oscillatory flow exhibited hyperplastic neointima, reduced endothelial continuity, and increased SMC-like cells and ECM, indicating superficial erosion-prone lesions. In addition, oscillatory flow significantly induced EndMT, whereas inhibition of EndMT ameliorated the formation of superficial erosion-prone lesions. Bioinformatic data analyses and in vitro studies showed a remarkable reduction in anti-EndMT KLF2 and KLF4 in a DNA methyltransferase (DNMT)-dependent manner, and the suppression of DNMTs attenuated oscillatory flow-induced EndMT and superficial erosion-prone lesions.

Conclusions: Chronic oscillatory flow causes superficial erosion-prone lesions by activating EndMT in a DNMT-dependent manner. Our findings highlight a promising therapeutic strategy for the prevention of superficial erosions.