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bioRxiv · 10.64898/2026.04.14.718463

A Biphasic Effect of Alcohol on Endothelial Plasticity Through Regulation of Endothelial-to-Mesenchymal Transition

Liu, W.·Gusti, Y.·Athar, F.·Rajendran, N. K.·Cahill, P. A.·Redmond, E. M.
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Abstract

BackgroundAlcohol consumption influences cardiovascular disease, but whether it does so by affecting endothelial plasticity is unknown. We tested whether alcohol regulates endothelial-to-mesenchymal transition (EndMT) to influence arterial pathology. MethodsHCAEC and HUVEC were exposed to inflammatory cytokines (TGF{beta} {+/-} IL1{beta}) or hypoxia in the presence of ethanol (0-100 mM). EndMT was assessed by changes in cell marker expression, SNAIL levels, and migration assays. In vivo, carotid ligation was performed in mice gavaged with/without either daily moderate ethanol (2-drink equivalent/d) or episodic binge exposure (7-drink equivalent, 2 days/week) and myo-endothelial cell population assessed. ResultsCytokines and hypoxia induced EndMT in vitro, characterized by loss of endothelial markers, increased mesenchymal markers, elevated SNAIL, and enhanced migratory capacity. Low-to-moderate dose ethanol (5-25 mM) attenuated these changes, preserving endothelial phenotype, whereas high dose ethanol (50-100 mM) either had no effect or exacerbated EndMT. The inhibitory effect of moderate ethanol on cytokine- and hypoxia-induced changes in SMA and Cdh5 expression was abrogated by {gamma}-secretase inhibition, consistent with involvement of Notch signaling. Carotid ligation induced neointimal formation and accumulation of myo-endothelial cells indicative of EndMT. Daily moderate ethanol significantly attenuated neointimal hyperplasia and diminished the myo-endothelial cell population, whereas in contrast, episodic binge ethanol exposure increased pathologic remodeling and myo-endothelial cell abundance. ConclusionsAlcohol modulates endothelial trans-differentiation in a biphasic manner. Low-to-moderate alcohol exposure suppresses EndMT and limits pathological remodeling, whereas binge-level exposure promotes these processes. These findings identify regulation of endothelial plasticity as a potential novel mechanism linking alcohol consumption patterns to vascular disease risk. NEW AND NOTEWORTHYWe identify a previously unrecognized biphasic effect of alcohol on endothelial phenotypic plasticity. Low-to-moderate dose alcohol suppresses endothelial-to-mesenchymal transition (EndMT), whereas high-level (binge) exposure promotes this pro-atherogenic process. Given the central role of EndMT in vascular remodelling and atherosclerosis, these findings provide a mechanistic framework linking alcohol consumption patterns and cardiovascular disease risk - potentially explaining both the protective effect at low/moderate levels, and the detrimental impact of heavy alcohol use. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/718463v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1febae2org.highwire.dtl.DTLVardef@9f5ff1org.highwire.dtl.DTLVardef@153ea69org.highwire.dtl.DTLVardef@42b1ed_HPS_FORMAT_FIGEXP M_FIG C_FIG Injurious stimuli can trigger endothelial cells (EC) to undergo endothelial-to-mesenchymal transition (EndMT) that contributes to arterial remodeling and disease. EndMT is regulated in a biphasic manner by alcohol with low-to-moderate levels (1-3 drink equivalent) suppressing EndMT and attenuating vascular remodeling, whereas higher level/binge exposure (7 drink equivalent) promotes these processes. Graphic created using Biorender.

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Liu, W., Gusti, Y., Athar, F., Rajendran, N. K., Cahill, P. A., Redmond, E. M.. 2026-04-16. A Biphasic Effect of Alcohol on Endothelial Plasticity Through Regulation of Endothelial-to-Mesenchymal Transition. https://doi.org/10.64898/2026.04.14.718463

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