Atherosclerotic Plaque Crystals Induce Endothelial Dysfunction

TL;DR

This study shows how cholesterol and urate crystals harm blood vessel cells, causing inflammation and mitochondrial damage, which may trigger early atherosclerosis.

Contribution

The study reveals a novel bioenergetic vulnerability in endothelial cells caused by crystal-induced mitochondrial dysfunction.

Findings

Cholesterol and monosodium urate crystals activate NF-κB and STAT3 pathways in endothelial cells.

Crystal exposure leads to mitochondrial dysfunction and impaired respiratory capacity.

Crystals promote endothelial adhesion molecule expression and neutrophil adhesion.

Abstract

Endothelial dysfunction is an early driver of atherosclerosis, yet the direct impact of endogenous crystals such as cholesterol crystals and monosodium urate on endothelial activation remains incompletely understood. In this study, we examine how crystalline stimuli modulate human umbilical vein endothelial cells by assessing inflammatory signaling, mitochondrial respiration, and neutrophil recruitment. Using dose- and time-controlled experiments, we show that CC and MSU are internalized by endothelial cells, activating NF-κB and STAT3 signaling pathways and inducing a robust pro-inflammatory cytokine profile. Notably, CC caused marked mitochondrial dysfunction, evidenced by impaired respiratory capacity and loss of membrane potential, revealing a novel bioenergetic vulnerability in endothelial cells. Both direct crystal stimulation and exposure to crystal-primed conditioned media triggered endothelial adhesion molecule expression and promoted neutrophil adhesion, indicating that soluble mediators released upon crystal stimulation can propagate vascular inflammation. These findings demonstrate that crystalline stimuli are potent vascular danger signals capable of driving endothelial inflammation, mitochondrial impairment, and immune cell engagement, which are hallmarks of early atherogenesis. By elucidating these multifaceted endothelial responses, this study provides important mechanistic insights into how crystal-induced signals may contribute to vascular dysfunction and the early stages of atherogenesis.

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