Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummary
Background & Aims: Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are 2 principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanc...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X25000281 |
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| author | Guangbo Wu Qiang Fan Min Chen Guqing Luo Zhenghao Wu Jinbo Zhao Jiayun Lin Chihao Zhang Hongjie Li Xiaoliang Qi Haizhong Huo Lei Zheng Meng Luo |
| author_facet | Guangbo Wu Qiang Fan Min Chen Guqing Luo Zhenghao Wu Jinbo Zhao Jiayun Lin Chihao Zhang Hongjie Li Xiaoliang Qi Haizhong Huo Lei Zheng Meng Luo |
| author_sort | Guangbo Wu |
| collection | DOAJ |
| description | Background & Aims: Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are 2 principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanced stages of cirrhosis, the fibrotic process in the liver becomes irreversible, leading to persistent and intractable increases in intrahepatic vascular resistance. Arterial remodeling emerges as a crucial mechanism driving the hyperdynamic splanchnic circulation. Therefore, ameliorating the hyperdynamic splanchnic circulation has become an indispensable component of PHT therapeutic strategies. Methods: Liver cirrhosis with PHT was induced in the rats by common bile duct ligation (BDL). Based on the transcriptomic sequencing of the mesenteric arteries, we investigated the effects and mechanisms of metformin on the arterial remodeling at different stages of cirrhosis. We further validated potential molecular mechanisms through in vitro experiments using the A7r5 smooth muscle cell line and primary vascular smooth muscle cells (VSMCs). Results: Our findings revealed the beneficial effects of metformin on liver cirrhosis and PHT in rats following BDL for 4 and 6 weeks. Metformin was observed to ameliorate PHT and splanchnic hyperdynamic circulation in BDL rats, even in the advanced stages of liver cirrhosis. This effect was evidenced by reduced portal pressure and cardiac output, decreased superior mesenteric artery (SMA) flow, accompanied by improvements in systemic vascular resistance and SMA resistance. Moreover, chronic inflammation in BDL rats was alleviated by metformin, which might inhibit the driving factors of angiogenesis and arterial remodeling. Notably, SMA dilation and arterial remodeling in BDL rats were potent alleviated following metformin treatment. Metformin ameliorated arterial remodeling in BDL rats by inhibiting the dedifferentiation of contractile VSMCs, resulting in the upregulation of contractile protein expressions such as alpha-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α). Platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFR-β) signaling exerted crucial roles in regulating the VSMCs cell phenotype. Activation of AMP-activated protein kinase (AMPK) by metformin blocked the downstream pathway of PDGF-BB/PDGFRβ. Furthermore, in vitro cell experiments, VSMCs were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C. We revealed the molecular mechanism that metformin inhibited the phenotypic switching of A7r5 cells induced by PDGF-BB and primary VSMCs from BDL rats, which was mediated by activating AMPK to enhance the expression of contractile protein α-SMA. These findings suggest that AMPK can ameliorate the progression of arterial remodeling during PHT via suppressing the PDGF-BB/PDGFRβ signaling pathway, thereby offering novel insights into seek PHT treatment approaches. Conclusions: Our findings revealed that metformin exerts its effects by activating the AMPK pathway, inhibiting the dedifferentiation of contractile VSMCs in the splanchnic arteries, and improving arterial remodeling, thereby ameliorating PHT and splanchnic hyperdynamic circulation in cirrhotic rats. |
| format | Article |
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| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-21862d7adb0c40fcb8144d3afdf9adc82025-08-20T02:15:41ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119610148710.1016/j.jcmgh.2025.101487Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummaryGuangbo Wu0Qiang Fan1Min Chen2Guqing Luo3Zhenghao Wu4Jinbo Zhao5Jiayun Lin6Chihao Zhang7Hongjie Li8Xiaoliang Qi9Haizhong Huo10Lei Zheng11Meng Luo12Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaCorrespondence Address correspondence to: Dr Meng Luo, Dr Haizhong Huo, and Dr Lei Zheng, Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.; Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaCorrespondence Address correspondence to: Dr Meng Luo, Dr Haizhong Huo, and Dr Lei Zheng, Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.; Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaCorrespondence Address correspondence to: Dr Meng Luo, Dr Haizhong Huo, and Dr Lei Zheng, Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.; Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaBackground & Aims: Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are 2 principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanced stages of cirrhosis, the fibrotic process in the liver becomes irreversible, leading to persistent and intractable increases in intrahepatic vascular resistance. Arterial remodeling emerges as a crucial mechanism driving the hyperdynamic splanchnic circulation. Therefore, ameliorating the hyperdynamic splanchnic circulation has become an indispensable component of PHT therapeutic strategies. Methods: Liver cirrhosis with PHT was induced in the rats by common bile duct ligation (BDL). Based on the transcriptomic sequencing of the mesenteric arteries, we investigated the effects and mechanisms of metformin on the arterial remodeling at different stages of cirrhosis. We further validated potential molecular mechanisms through in vitro experiments using the A7r5 smooth muscle cell line and primary vascular smooth muscle cells (VSMCs). Results: Our findings revealed the beneficial effects of metformin on liver cirrhosis and PHT in rats following BDL for 4 and 6 weeks. Metformin was observed to ameliorate PHT and splanchnic hyperdynamic circulation in BDL rats, even in the advanced stages of liver cirrhosis. This effect was evidenced by reduced portal pressure and cardiac output, decreased superior mesenteric artery (SMA) flow, accompanied by improvements in systemic vascular resistance and SMA resistance. Moreover, chronic inflammation in BDL rats was alleviated by metformin, which might inhibit the driving factors of angiogenesis and arterial remodeling. Notably, SMA dilation and arterial remodeling in BDL rats were potent alleviated following metformin treatment. Metformin ameliorated arterial remodeling in BDL rats by inhibiting the dedifferentiation of contractile VSMCs, resulting in the upregulation of contractile protein expressions such as alpha-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α). Platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFR-β) signaling exerted crucial roles in regulating the VSMCs cell phenotype. Activation of AMP-activated protein kinase (AMPK) by metformin blocked the downstream pathway of PDGF-BB/PDGFRβ. Furthermore, in vitro cell experiments, VSMCs were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C. We revealed the molecular mechanism that metformin inhibited the phenotypic switching of A7r5 cells induced by PDGF-BB and primary VSMCs from BDL rats, which was mediated by activating AMPK to enhance the expression of contractile protein α-SMA. These findings suggest that AMPK can ameliorate the progression of arterial remodeling during PHT via suppressing the PDGF-BB/PDGFRβ signaling pathway, thereby offering novel insights into seek PHT treatment approaches. Conclusions: Our findings revealed that metformin exerts its effects by activating the AMPK pathway, inhibiting the dedifferentiation of contractile VSMCs in the splanchnic arteries, and improving arterial remodeling, thereby ameliorating PHT and splanchnic hyperdynamic circulation in cirrhotic rats.http://www.sciencedirect.com/science/article/pii/S2352345X25000281Arterial RemodelingLiver CirrhosisPhenotypic switching of VSMCsPortal HypertensionSplanchnic Hyperdynamic Circulation |
| spellingShingle | Guangbo Wu Qiang Fan Min Chen Guqing Luo Zhenghao Wu Jinbo Zhao Jiayun Lin Chihao Zhang Hongjie Li Xiaoliang Qi Haizhong Huo Lei Zheng Meng Luo Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummary Cellular and Molecular Gastroenterology and Hepatology Arterial Remodeling Liver Cirrhosis Phenotypic switching of VSMCs Portal Hypertension Splanchnic Hyperdynamic Circulation |
| title | Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummary |
| title_full | Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummary |
| title_fullStr | Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummary |
| title_full_unstemmed | Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummary |
| title_short | Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal HypertensionSummary |
| title_sort | activation of amp activated protein kinase by metformin inhibits dedifferentiation of platelet derived growth factor bb induced vascular smooth muscle cells to improve arterial remodeling in cirrhotic portal hypertensionsummary |
| topic | Arterial Remodeling Liver Cirrhosis Phenotypic switching of VSMCs Portal Hypertension Splanchnic Hyperdynamic Circulation |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X25000281 |
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