Sánchez Marrero Gloriani, Villa-Roel Nicolas, Li Feifei, Park Christian, Kang Dong-Won, Hekman Katherine E, Jo Hanjoong, Brewster Luke P
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States.
Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States.
Front Cardiovasc Med. 2023 Sep 7;10:1251141. doi: 10.3389/fcvm.2023.1251141. eCollection 2023.
Peripheral arterial disease (PAD) is an age-related medical condition affecting mostly muscular arteries of the limb. It is the 3 leading cause of atherosclerotic morbidity. The mechanical environment of endothelial cells (ECs) in PAD is characterized by disturbed blood flow (d-flow) and stiff extracellular matrices. In PAD, the stiffness of arteries is due to decreased elastin function and increased collagen content. These flow and stiffness parameters are largely missing from current models of PAD. It has been previously proven that ECs exposed to d-flow or stiff substrates lead to proatherogenic pathways, but the effect of both, d-flow and stiffness, on EC phenotype has not been fully investigated. In this study, we sought to explore the effect of sex on proatherogenic pathways that could result from exposing endothelial cells to a d-flow and stiff environment. We utilized the scRNA-seq tool to analyze the gene expression of ECs exposed to the different mechanical conditions both and . We found that male ECs exposed to different mechanical stimuli presented higher expression of genes related to fibrosis and d-flow . We validated our findings by exposing murine carotid arteries to d-flow via partial carotid artery ligation. Since women have delayed onset of arterial stiffening and subsequent PAD, this work may provide a framework for some of the pathways in which biological sex interacts with sex-based differences in PAD.
外周动脉疾病（PAD）是一种与年龄相关的病症，主要影响肢体的肌性动脉。它是动脉粥样硬化性发病的第三大主要原因。PAD中内皮细胞（ECs）的力学环境的特征是血流紊乱（d-flow）和细胞外基质僵硬。在PAD中，动脉的僵硬是由于弹性蛋白功能降低和胶原蛋白含量增加。目前的PAD模型在很大程度上缺少这些血流和僵硬参数。先前已证明，暴露于d-flow或僵硬基质的内皮细胞会导致动脉粥样硬化前通路，但d-flow和僵硬对内皮细胞表型的影响尚未得到充分研究。在本研究中，我们试图探索性别对内皮细胞暴露于d-flow和僵硬环境可能导致的动脉粥样硬化前通路的影响。我们利用单细胞RNA测序（scRNA-seq）工具分析了暴露于不同力学条件下的内皮细胞的基因表达。我们发现，暴露于不同力学刺激下的雄性内皮细胞呈现出与纤维化和d-flow相关的基因的更高表达。我们通过部分颈动脉结扎使小鼠颈动脉暴露于d-flow来验证我们的发现。由于女性动脉僵硬及随后的PAD发病延迟，这项工作可能为生物性别与PAD中基于性别的差异相互作用的一些通路提供一个框架。
