Biphasic Effect of Pirfenidone on Angiogenesis

Gan, Donghao1,2; Cheng, Wenxiang1; Ke, Liqing1; Sun, Antonia RuJia1; Jia, Qingyun3; Chen, Jianhai1; Xu, Zhanwang4; Xu, Juan5; Zhang, Peng1,6,7

2022-01-05

10.3389/fphar.2021.804327

FRONTIERS IN PHARMACOLOGY   影响因子和分区

1663-9812

Pirfenidone (PFD), a synthetic arsenic compound, has been found to inhibit angiogenesis at high concentrations. However, the biphasic effects of different PFD concentrations on angiogenesis have not yet been elucidated, and the present study used an in vitro model to explore the mechanisms underlying this biphasic response. The effect of PFD on the initial angiogenesis of vascular endothelial cells was investigated through a Matrigel tube formation assay, and the impact of PFD on endothelial cell migration was evaluated through scratch and transwell migration experiments. Moreover, the expression of key migration cytokines, matrix metalloproteinase (MMP)-2 and MMP-9, was examined. Finally, the biphasic mechanism of PFD on angiogenesis was explored through cell signaling and apoptosis analyses. The results showed that 10-100 mu M PFD has a significant and dose-dependent inhibitory effect on tube formation and migration, while 10 nM-1 mu M PFD significantly promoted tube formation and migration, with 100 nM PFD having the strongest effect. Additionally, we found that a high concentration of PFD could significantly inhibit MMP-2 and MMP-9 expression, while low concentrations of PFD significantly promoted their expression. Finally, we found that high concentrations of PFD inhibited EA.hy926 cell tube formation by promoting apoptosis, while low concentrations of PFD promoted tube formation by increasing MMP-2 and MMP-9 protein expression predominantly via the EGFR/p-p38 pathway. Overall, PFD elicits a biphasic effect on angiogenesis through different mechanisms, could be used as a new potential drug for the treatment of vascular diseases.

pirfenidone angiogenesis biphasic response vascular endothelial cells signaling pathways

SCI

英语

其他

National Key R&D Program of China[2018YFC1705205] ; Foreign cooperation project of Chinese Academy of Sciences[172644KYSB20190032] ; National Natural Science Foundation of China[92068117,81871809,8217151988] ; Guangdong Basic and Applied Basic Research Fund[2020B1515120052] ; Natural Science Foundation of Shandong Province["ZR2020KH011","ZR2021QH230"] ; Sanming Project of Medicine in Shenzhen[SZSM201808072] ; Development and Reform Commission of Shenzhen Municipality[XMHT20190106001] ; Bureau of Industry and Information Technology of Shenzhen[201908141541] ; Shenzhen International Collaborative Project[GJHZ20200731095009028] ; [92068117,81871809,8217151988]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000745811800001

FRONTIERS MEDIA SA

Web of Science

1.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Sch Med, Shenzhen, Peoples R China
3.Linyi Peoples Hosp, Ward Trauma Surg Dept 2, Linyi, Shandong, Peoples R China
4.Shandong Univ Tradit Chinese Med, Affiliated Hosp, Dept Orthoped, Jinan, Peoples R China
5.SijingHospital, Dept Stomatol, Shanghai, Peoples R China
6.Shenzhen Engn Res Ctr Med Bioact Mat, Shenzhen, Peoples R China
7.Univ Chinese Acad Sci, Beijing, Peoples R China

Gan, Donghao,Cheng, Wenxiang,Ke, Liqing,et al. Biphasic Effect of Pirfenidone on Angiogenesis[J]. FRONTIERS IN PHARMACOLOGY,2022,12.

Gan, Donghao.,Cheng, Wenxiang.,Ke, Liqing.,Sun, Antonia RuJia.,Jia, Qingyun.,...&Zhang, Peng.(2022).Biphasic Effect of Pirfenidone on Angiogenesis.FRONTIERS IN PHARMACOLOGY,12.

Gan, Donghao,et al."Biphasic Effect of Pirfenidone on Angiogenesis".FRONTIERS IN PHARMACOLOGY 12(2022).