Tetramethylpyrazine Ameliorates Peritoneal Angiogenesis by Regulating VEGF/Hippo/YAP Signaling

血管生成 CTGF公司 血管内皮生长因子 癌症研究 河马信号通路 新生血管 细胞生物学 信号转导 医学 化学 生长因子 内科学 生物 受体 血管内皮生长因子受体
作者
Xiaolin Zhu,Yun Shan,Manshu Yu,Jun Shi,Lei Tang,Huimin Cao,Meixiao Sheng
出处
期刊:Frontiers in Pharmacology [Frontiers Media]
卷期号:12 被引量:18
标识
DOI:10.3389/fphar.2021.649581
摘要

Angiogenesis of human peritoneal vascular endothelial cells (HPVECs), linked to vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling, is a complication of peritoneal fibrosis (PF). Hippo/YAP signaling interacts with VEGF/VEGFR2 signaling, but the effect on peritoneal angiogenesis and PF has not been studied. We tested VEGF/Hippo/YAP inhibition by tetramethylpyrazine (TMP) in PF mice and HPVECs. This treatment ameliorated peritoneal dialysis (PD)–induced angiogenesis and PF. In mice, PF was associated with upregulation of VEGF, and TMP ameliorated submesothelial fibrosis, perivascular bleeding, and Collagen I abundance. In HPVECs, angiogenesis occurred due to human peritoneal mesothelial cells (HPMCs)–conditioned medium, and TMP alleviated HPVECs migration, tube formation, and YAP nuclear translocation. YAP knockdown PF mouse and HPVEC models were established to further confirm our finding. YAP deletion attenuated the PD-induced or VEGF-induced increase in angiogenesis and PF. The amount of CYR61 and CTGF was significantly less in the YAP knockdown group. To study the possibility that TMP could benefit angiogenesis, we measured the HPVECs migration and tube formation and found that both were sharply increased in YAP overexpression; TMP treatment partly abolished these increases. As well, the amount of VEGFR localized in the trans-Golgi network was lower by double immunofluorescence; VEGFR and its downstream signaling pathways including p-ERK, p-P38, and p-Akt were more in HPVECs with YAP overexpression. Overall, TMP treatment ameliorated angiogenesis, PF, and peritoneum injury. These changes were accompanied by inhibition of VEGF/Hippo/YAP.
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