Heo Kyung-Sun, Phan Lan Phuong, Le Nhi Thi Thao, Jin Yujin
Department of Pharmacology, Chungnam National University, College of Pharmacy, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea.
Arch Pharm Res. 2025 Apr;48(4):305-332. doi: 10.1007/s12272-025-01542-4. Epub 2025 Apr 29.
Endothelial dysfunction plays a pivotal role in the pathogenesis of various cardiovascular diseases (CVDs), including atherosclerosis, hypertension, heart failure, stroke, and peripheral artery disease. It disrupts vascular homeostasis, leading to reduced nitric oxide (NO) bioavailability, increased oxidative stress, and chronic inflammation, all of which collectively drive vascular damage, atherosclerotic plaque formation, and thrombosis. Additionally, shear stress-induced alterations in blood flow patterns, particularly disturbed flow (d-flow), aggravate endothelial dysfunction. Furthermore, the endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells acquire mesenchymal-like properties, contributes to vascular remodeling and accelerates CVD progression.This review explores the significant role of epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs (ncRNAs), which serve as critical regulators of endothelial function in response to shear stress in endothelial dysfunction and the development of atherosclerosis. Furthermore, we discuss the pivotal role of endothelial dysfunction in cardiovascular and metabolic diseases, emphasizing the need for innovative therapeutic strategies beyond conventional treatments. In particular, we highlight the endothelial-protective mechanisms of emerging pharmacological agents, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, along with supporting clinical evidence demonstrating their efficacy in improving endothelial function and reducing cardiovascular risk.
内皮功能障碍在各种心血管疾病（CVDs）的发病机制中起关键作用，这些疾病包括动脉粥样硬化、高血压、心力衰竭、中风和外周动脉疾病。它破坏血管稳态，导致一氧化氮（NO）生物利用度降低、氧化应激增加和慢性炎症，所有这些共同驱动血管损伤、动脉粥样硬化斑块形成和血栓形成。此外，剪切应力诱导的血流模式改变，特别是紊乱血流（d-flow），会加重内皮功能障碍。此外，内皮向间充质转化（EndMT），即内皮细胞获得间充质样特性的过程，有助于血管重塑并加速CVD进展。本综述探讨了表观遗传机制的重要作用，如DNA甲基化、组蛋白修饰和非编码RNA（ncRNAs），它们在内皮功能障碍和动脉粥样硬化发展过程中作为内皮功能响应剪切应力的关键调节因子。此外，我们讨论了内皮功能障碍在心血管和代谢疾病中的关键作用，强调了超越传统治疗的创新治疗策略的必要性。特别是，我们强调了新兴药物制剂的内皮保护机制，包括前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）抑制剂、胰高血糖素样肽-1受体激动剂（GLP-1RAs）和钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，以及支持它们在改善内皮功能和降低心血管风险方面疗效的临床证据。
