Department of Physiology and Pathophysiology, Cardiovascular Research Centre, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
Cell Mol Life Sci. 2023 Jan 11;80(2):38. doi: 10.1007/s00018-022-04623-5.
Vascular endothelial dysfunction is regarded as an early event of hypertension. Galectin-3 (Gal-3) is known to participate in various pathological processes. Whilst previous studies showed that inhibition of Gal-3 effectively ameliorates angiotensin II (Ang II)-induced atherosclerosis or hypertension, it remains unclear whether Ang II regulates Gal-3 expression and actions in vascular endothelium.
Using techniques of molecular biology and myograph, we investigated Ang II-mediated changes in Gal-3 expression and activity in thoracic aortas and mesenteric arteries from wild-type and Gal-3 gene deleted (Gal-3) mice and cultured endothelial cells.
The serum level of Gal-3 was significantly higher in hypertensive patients or in mice with chronic Ang II-infusion. Ang II infusion to wild-type mice enhanced Gal-3 expression in the aortic and mesenteric arteries, elevated systolic blood pressure and impaired endothelium-dependent relaxation of the thoracic aortas and mesenteric arteries, changes that were abolished in Gal-3 mice. In human umbilical vein endothelial cells, Ang II significantly upregulated Gal-3 expression by promoting nuclear localization of Yes-associated protein (YAP) and its interaction with transcription factor Tead1 with enhanced YAP/Tead1 binding to Gal-3 gene promoter region. Furthermore, Gal-3 deletion augmented the bioavailability of nitric oxide, suppressed oxidative stress, and alleviated inflammation in the thoracic aorta of Ang II-infused mice or endothelial cells exposed to Ang II.
Our results demonstrate for the first time that Ang II upregulates Gal-3 expression via increment in YAP nuclear localization in vascular endothelium, and that Gal-3 mediates endothelial dysfunction contributing to the development of hypertension.
血管内皮功能障碍被认为是高血压的早期事件。半乳糖凝集素-3（Gal-3）已知参与各种病理过程。虽然先前的研究表明抑制 Gal-3 可有效改善血管紧张素 II（Ang II）诱导的动脉粥样硬化或高血压，但尚不清楚 Ang II 是否调节血管内皮中 Gal-3 的表达和作用。
使用分子生物学和肌动图技术，我们研究了 Ang II 介导的野生型和 Gal-3 基因缺失（Gal-3）小鼠胸主动脉和肠系膜动脉以及培养的内皮细胞中 Gal-3 表达和活性的变化。
高血压患者或慢性 Ang II 输注小鼠的血清 Gal-3 水平明显升高。Ang II 输注到野生型小鼠中增强了主动脉和肠系膜动脉中 Gal-3 的表达，升高了收缩压并损害了胸主动脉和肠系膜动脉的内皮依赖性舒张，这些变化在 Gal-3 小鼠中被消除。在人脐静脉内皮细胞中，Ang II 通过促进 Yes 相关蛋白（YAP）的核定位及其与转录因子 Tead1 的相互作用，显著上调 Gal-3 表达，增强 YAP/Tead1 结合到 Gal-3 基因启动子区域。此外，Gal-3 缺失增加了胸主动脉中 Ang II 输注或内皮细胞暴露于 Ang II 时一氧化氮的生物利用度，抑制氧化应激并减轻炎症。
我们的结果首次表明，Ang II 通过增加血管内皮细胞中 YAP 的核定位来上调 Gal-3 表达，并且 Gal-3 介导内皮功能障碍导致高血压的发展。
