{"title":"Atherosclerotic Plaque Crystals Induce Endothelial Dysfunction.","authors":"Jishamol Thazhathveettil, Sherin Aloysius Gomez, Deborah Olaoseeji, Rongrong Wu, Allan Sirsjö, Geena Varghese Paramel","doi":"10.3390/ijms26199758","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 19","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12525030/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Molecular Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/ijms26199758","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).