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

Abstract

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.

The regulation of yes-associated protein/transcriptional coactivator with PDZ-binding motif and their roles in vascular endothelium

“…Bosutinib, a tyrosine kinase inhibitor, significantly decreased the level of the phosphorylation of YAP at tyrosine 357 (Y357) and YAP activation to alleviate endothelium injury and the development of atherosclerosis (25). Likewise, salvianolic acid B, harmine and tetramethylpyrazine, the extracts from the traditional medicinal plants, inhibited YAP nuclear translocation and activation, and thus played a potent atheroprotective role (8,9,53). These inhibitor and extracts from the traditional medicinal plants might serve as potential therapeutical candidates for improving endothelial function and cardiovascular diseases via regulating the YAP/TAZ pathway.…”

Verteporfin-mediated on/off photoswitching functions synergistically to treat choroidal vascular diseases

“…VP can inhibit YAP transcriptional activity in the Hippo pathway, resulting in the regulation of tissue development. Emerging studies have revealed an underlying convergence between VEGF and Hippo-YAP signaling, which has yet to be utilized in clinical applications [ [19] , [20] , [21] , [22] ]. YAP signaling could act as a hinge to mediate the downstream proangiogenic phenotype.…”

Endoglin aggravates peritoneal fibrosis by regulating the activation of TGF-β/ALK/Smads signaling

“…Williams et al (2002) performed the first comprehensive cross-sectional analysis of the morphological changes in the peritoneal membranes of patients undergoing PD and showed that the density of blood vessels per unit length of peritoneum was significantly higher for patients with peritoneal membrane function failure and was correlated with the degree of fibrosis. Furthermore, Zhu et al (2021) proved that Tetramethylpyrazine (TMP) treatment inhibited peritoneal angiogenesis and also ameliorated peritoneal thickening and collagen deposition. These findings suggest that antiangiogenic therapy may serve as a potential modality for preventing or reversing PF.…”