Wang Wei-Li, Shih Yu-Tsung, Wei Shu-Yi, Chiu Jeng-Jiann
Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
J Biomed Sci. 2025 Sep 1;32(1):83. doi: 10.1186/s12929-025-01177-z.
Aging is the foremost risk factor for metabolic syndrome and atherosclerosis, which is a principal cause of cardiovascular diseases (CVDs). Vascular endothelial cells (ECs), which line the vascular intima, play a central role in maintaining vascular homeostasis. Their dysfunction, marked by impaired barrier function, inflammation, and metabolic dysregulation, constitutes an early and pivotal event in atherogenesis. As key sensors of hemodynamic forces, ECs are constantly exposed to blood flow-induced shear stress, which exert divergent effects on metabolism depending on the flow pattern. Laminar flow with relatively high shear stress (LS), as a critical atheroprotective factor, maintains EC quiescence and promotes anti-inflammatory responses and antioxidant defense, whereas disturbed flow with low and oscillatory shear stress (OS), induces the athero-susceptible signaling network to activate glycolysis and inflammation in ECs. While genetic, epigenetic, and molecular signaling mechanisms in EC physiology and pathophysiology have been extensively explored, the crucial role of EC metabolism in EC dysfunction and atherogenesis remains largely understudied. By serving as precursors, intermediates, and end products of cellular processes, metabolites offer a dynamic snapshot of endothelial metabolic states under both physiological and pathophysiological conditions. With aging, ECs undergo profound metabolic reprogramming, including disrupted glycolysis, mitochondrial dysfunction, and altered redox homeostasis. In healthy vasculature, ECs maintain quiescence and metabolic homeostasis, primarily relying on glycolysis for energy. With aging, the gradual accumulation of atherosclerotic risk factors, including oxidative stress, inflammation, dyslipidemia, and hyperglycemia, drives metabolic reprogramming in ECs, particularly in regions exposed to disturbed flow with OS, ultimately leading to EC dysfunction and atherosclerosis. This review summarizes recent advances in age-related metabolic reprogramming in ECs and its contribution to atherosclerosis, particularly focusing on the dysregulation of glycolysis, fatty acid metabolism, amino acid metabolism, and mitochondrial respiration induced by age and fluid shear stress. This review also outlines recent methodologies for profiling EC metabolism, and discusses potential therapeutic applications of targeting EC metabolism to prevent or delay the development of atherosclerosis.
衰老代谢综合征和动脉粥样硬化的首要风险因素，而动脉粥样硬化是心血管疾病（CVD）的主要原因。血管内皮细胞（ECs）排列在血管内膜，在维持血管稳态中起核心作用。其功能障碍以屏障功能受损、炎症和代谢失调为特征，是动脉粥样硬化发生的早期关键事件。作为血流动力学力的关键传感器，ECs不断受到血流诱导的剪切应力作用，根据血流模式，剪切应力对代谢产生不同影响。具有相对高剪切应力（LS）的层流作为一种关键的抗动脉粥样硬化保护因子，维持ECs的静止状态，促进抗炎反应和抗氧化防御，而具有低和振荡剪切应力（OS）的紊乱血流则诱导动脉粥样硬化易感信号网络激活ECs中的糖酵解和炎症。虽然EC生理学和病理生理学中的遗传、表观遗传和分子信号机制已得到广泛研究，但EC代谢在EC功能障碍和动脉粥样硬化中的关键作用仍 largely未得到充分研究。代谢物作为细胞过程的前体、中间体和终产物，提供了生理和病理生理条件下内皮代谢状态的动态快照。随着衰老，ECs经历深刻的代谢重编程，包括糖酵解紊乱、线粒体功能障碍和氧化还原稳态改变。在健康血管中，ECs维持静止和代谢稳态，主要依靠糖酵解获取能量。随着衰老，包括氧化应激、炎症、血脂异常和高血糖在内的动脉粥样硬化风险因素逐渐积累，驱动ECs中的代谢重编程，特别是在暴露于具有OS的紊乱血流的区域，最终导致EC功能障碍和动脉粥样硬化。本综述总结了ECs中与年龄相关的代谢重编程及其对动脉粥样硬化的贡献的最新进展，特别关注年龄和流体剪切应力诱导的糖酵解、脂肪酸代谢、氨基酸代谢和线粒体呼吸的失调。本综述还概述了最近用于分析EC代谢的方法，并讨论了靶向EC代谢以预防或延缓动脉粥样硬化发展的潜在治疗应用。
