2. Academic Validation
  3. Angiotensin II depends on hippo/YAP signaling to reprogram angiogenesis and promote liver fibrosis

Angiotensin II depends on hippo/YAP signaling to reprogram angiogenesis and promote liver fibrosis

  • Cell Signal. 2024 Nov:123:111355. doi: 10.1016/j.cellsig.2024.111355.
Yanan Zhou 1,  Pan Liang 2,  Tao Bi 1,  Bo Tang 3,  Xiaoning Zhu 4,  Xinyue Liu 1,  Hong Wang 1,  Hongping Shen 1,  Qin Sun 1,  Sijin Yang 5,  Wei Ren 6
Affiliations

Affiliations

  • 1 National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China.
  • 2 National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China; State Key Laboratories for Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 853, China.
  • 3 Department of Pathology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
  • 4 Department of Hepatobiliary, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
  • 5 National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China; State Key Laboratories for Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 853, China. Electronic address: ysjimn@swmu.edu.cn.
  • 6 National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou 646000, China. Electronic address: renwei1991@swmu.edu.cn.
PMID: 39173854 DOI: 10.1016/j.cellsig.2024.111355
Abstract

Liver fibrosis is a chronic pathological process in which the abnormal proliferation of connective tissue is induced by various pathogenic factors. During the process of fibrosis, excessive angiogenesis is observed. Physiological angiogenesis has the potential to impede the progression of liver fibrosis through augmenting matrix metalloenzyme activity; however, pathological angiogenesis can exacerbate liver fibrosis by promoting collagen accumulation. Therefore, a key scientific research focus in the treatment of liver diseases is to search for the "on-off" mechanism that regulates angiogenesis from normal proliferation to pathological proliferation. In this study, we found that excessive angiogenesis appeared during the initial phase of hepatic fibrosis without mesenchymal characteristics. In addition, angiogenesis accompanied by significant endothelial-to-mesenchymal transition (EndMT) was observed in mice after the intraperitoneal injection of angiotensin II (Ang II). Interestingly, the changes in Yes-associated protein (YAP) activity in endothelial cells (ECs) can affect the regulation of angiogenesis by Ang II. The results of in vitro experiments revealed that the regulatory influence of Ang II on ECs was significantly attenuated upon suppression of YAP activity. Furthermore, the function of Ang II in regulating angiogenesis during fibrosis was investigated in liver-specific transgenic mice. The results revealed that Ang II gene deletion could restrain liver fibrosis and EndMT. Meanwhile, Ang II deletion downregulated the profibrotic YAP signaling pathway in ECs. The small molecule AT1R agonist olmesartan targeting Ang II-YAP signaling could also alleviate liver fibrosis. In conclusion, this study identified Ang II as a pivotal regulator of EndMT during the progression of liver fibrosis and evaluated the therapeutic effect of the Ang II-targeted drug olmesartan on liver fibrosis.

Keywords

Angiogenesis; Angiotensin II; Endothelial-to-mesenchymal transition; Hippo/YAP; Liver fibrosis; Olmesartan.

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