Zhao Jiani, Xiong Yacheng, Liu Yu, Ling Jin, Liu Shuai, Wang Wei
Department of General and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
Mol Cell Biochem. 2025 Apr;480(4):2423-2435. doi: 10.1007/s11010-024-05115-9. Epub 2024 Sep 9.
Previous large-scale genetic studies have prioritized the causal genes piezo type mechanosensitive ion channel component 1 (PIEZO1) and castor zinc finger 1 (CASZ1) associated with varicose veins (VVs). This study aims to evaluate their roles in both clinical and experimental VVs. In this study, we investigated abundance of PIEZO1 and CASZ1 in both varicose and normal veins from the same patients. Yoda1 (a selective PIEZO1 agonist, 2.6 mg/kg/day) or vehicle was administered intraperitoneally for 3 weeks to evaluate the effect of PIEZO1 activation on experimental VVs. Subsequently, endothelial Piezo1 deletion mice (Piezo1 mice) were generated to explored the role of endothelial PIEZO1 on VVs. Laser speckle imaging, flow cytometry, cell tracing with Evans blue or rhodamine-6G, and histopathological staining were utilized to evaluate the pathophysiology of VVs. Our results showed that mRNA expression of PIEZO1, but not CASZ1, was abundant and increased in clinical VVs. The Piezo1 mice revealed endothelium-specific expression of PIEZO1 in mice veins. By establishing iliac vein ligation-induced VVs in mice, Yoda1 exacerbated experimental VVs with increased inflammatory cell infiltration. Subsequently, endothelial Piezo1 deletion (Piezo1 mice) alleviated experimental VVs and vascular remodeling by directly reducing vascular permeability and leukocyte-endothelium interactions compared to the control (Piezo1 mice). PIEZO1 is highly expressed in clinical VVs, meanwhile, activation or inhibition of PIEZO1 exerts a remarkable effect on experimental VVs. Furthermore, Piezo1 may constitute a potential therapeutic approach for the medical treatment of VVs.
以往的大规模基因研究已将与静脉曲张（VV）相关的因果基因——压电型机械敏感离子通道组分1（PIEZO1）和蓖麻锌指蛋白1（CASZ1）作为重点研究对象。本研究旨在评估它们在临床和实验性静脉曲张中的作用。在本研究中，我们调查了同一患者曲张静脉和正常静脉中PIEZO1和CASZ1的丰度。腹腔注射Yoda1（一种选择性PIEZO1激动剂，2.6毫克/千克/天）或赋形剂，持续3周，以评估PIEZO1激活对实验性静脉曲张的影响。随后，构建内皮细胞Piezo1基因缺失小鼠（Piezo1小鼠），以探究内皮PIEZO1在静脉曲张中的作用。利用激光散斑成像、流式细胞术、伊文思蓝或罗丹明-6G细胞示踪以及组织病理学染色来评估静脉曲张的病理生理学。我们的结果显示，临床静脉曲张中PIEZO1的mRNA表达丰富且增加，而CASZ1并非如此。Piezo1小鼠显示出小鼠静脉中PIEZO1的内皮特异性表达。通过在小鼠中建立髂静脉结扎诱导的静脉曲张，Yoda1加剧了实验性静脉曲张，炎症细胞浸润增加。随后，与对照（Piezo1小鼠）相比，内皮Piezo1基因缺失（Piezo1小鼠）通过直接降低血管通透性和白细胞与内皮细胞的相互作用，减轻了实验性静脉曲张和血管重塑。PIEZO1在临床静脉曲张中高表达，同时，PIEZO1的激活或抑制对实验性静脉曲张有显著影响。此外，Piezo1可能构成一种治疗静脉曲张的潜在医学方法。
