Bai Jing, Yang Yujuan
Department of Geriatric Cardiovascular Medicine, Shaanxi Provincial People's Hospital, No. 256, Youyi West Road, Xi'an, 710068, China.
J Mol Histol. 2025 May 19;56(3):158. doi: 10.1007/s10735-025-10443-1.
The Hippo/YAP signaling pathway is closely related to the occurrence and development of cardiovascular diseases. However, it's still unclear whether this pathway plays a certain role in hypertension. In this study, aortic morphology and function in spontaneously hypertensive rats (SHR) were comprehensively evaluated using Wistar-Kyoto rats (WKY) as controls. Results indicated that the aorta of SHRs have distinct changes in pathological structure. Furthermore, the proliferative activity of vascular smooth muscle cells (VSMCs) was enhanced, with vascular fibrosis being aggravated. Immunohistochemical analysis revealed that SHRs exhibited high expression of Yes-Associated Protein (YAP). Western Blot analysis showed that cytoplasmic YAP and TAZ expression decreased in hypertensive rats, indicating that YAP/TAZ nuclear transfer increased and Hippo/YAP signaling pathway had been activated. The cell function experiments of VSMCs extracted from rat aorta showed that the cell viability and proliferation ability of VSMCs in SHRs were enhanced, the expression of Fibronectin and collagen I was increased, and vascular fibrosis was aggravated. siRNA-YAP (si-YAP) can reverse the above phenomenon in VSMCs. Knockdown of YAP can inhibit Foxm1 expression. As an inhibitor of large tumor suppressor kinases LAST1/2, GA-107 can inhibit the phosphorylation level of YAP, increase blood pressure, aggravate aortic pathomorphological changes, promote VSMCs proliferation and vascular fibrosis, and thus aggravate hypertension symptoms in SHRs. However, these effects of GA-107 can be antagonized by inhibiting Foxm1 with thiosulfathiazole (Thio). Conclusively, Hippo/YAP signaling pathway promotes vascular remodeling through the regulation of Foxm1 and causes hypertension.
河马/Yes相关蛋白（YAP）信号通路与心血管疾病的发生和发展密切相关。然而，该通路在高血压中是否发挥一定作用仍不清楚。在本研究中，以Wistar-Kyoto大鼠（WKY）作为对照，全面评估了自发性高血压大鼠（SHR）的主动脉形态和功能。结果表明，SHR的主动脉病理结构有明显改变。此外，血管平滑肌细胞（VSMC）的增殖活性增强，血管纤维化加重。免疫组织化学分析显示，SHR中Yes相关蛋白（YAP）表达较高。蛋白质印迹分析表明，高血压大鼠细胞质中YAP和转录共激活因子TAZ表达降低，表明YAP/TAZ核转位增加，河马/YAP信号通路被激活。从大鼠主动脉提取的VSMC细胞功能实验表明，SHR中VSMC的细胞活力和增殖能力增强，纤连蛋白和I型胶原表达增加，血管纤维化加重。小干扰RNA-YAP（si-YAP）可逆转VSMC中的上述现象。敲低YAP可抑制叉头框蛋白M1（Foxm1）表达。作为大肿瘤抑制激酶LAST1/2的抑制剂，GA-107可抑制YAP的磷酸化水平，升高血压，加重主动脉病理形态学改变，促进VSMC增殖和血管纤维化，从而加重SHR的高血压症状。然而，GA-107的这些作用可被硫代磺胺噻唑（Thio）抑制Foxm1所拮抗。总之，河马/YAP信号通路通过调节Foxm1促进血管重塑并导致高血压。
