{
  "abstract": "Background Capillarisation of liver sinusoidal endothelial cells (LSECs) constitutes an early pathological event that promotes hepatic stellate cell activation and initiates liver fibrogenesis. Previous studies suggest that Ras-associated protein 1A (RAP1A) might be involved in liver fibrosis. However, the role of RAP1A in LSEC capillarisation remains unclear.Objective This study aimed to investigate the role of the endothelial GTPase RAP1A in sinusoidal capillarisation and liver fibrosis.Design Liver fibrosis models were induced by HFHCD, CDAHFD, CCl 4 or DDC treatment. EC-specific Rap1a knockout (Rap1aΔEC) mice were generated by breeding Rap1afl/fl mice with Cdh5-Cre mice. Therapeutic intervention was performed using the RAP1 activator 8-pCPT-2′-O-Me-cAMP. LSEC capillarisation, along with the extent of liver fibrosis and inflammation, was evaluated.Results RAP1A expression in LSECs was downregulated in all murine fibrosis models, as well as in primary LSECs undergoing spontaneous capillarisation during in vitro culturing. Young Rap1aΔEC mice exhibited spontaneous capillarisation, which progressed to liver fibrosis with age. Endothelial Rap1a deficiency exacerbated sinusoidal capillarisation and liver fibrosis in CCl4-/DDC-treated mice. Mechanistically, RAP1A loss promoted RAF1 degradation via the ubiquitin-proteasome pathway, enhancing nuclear translocation of Notch intracellular domain (NICD) and activating Notch signalling. Pharmacological activation of RAP1A attenuated LSEC capillarisation and mitigated liver fibrosis in CCl4-/DDC-induced models.Conclusion Endothelial Rap1a deficiency aggravates capillarisation and liver fibrosis by activating Notch signalling through RAF1 degradation. These findings indicate that Rap1a is essential for maintaining LSEC homeostasis and represents a potential intervention target for liver fibrosis.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Guangwen Chen"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Peking University People’s Hospital, Beijing, China"
      ],
      "name": "Weiming Dai"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Junjun Wang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Zhenyang Shen"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Yuecheng Guo"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Qichao Ge"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Hanjing Zhangdi"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Jianxiang Wang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Zhuqiong Lu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Qingqing Zhang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Yufei Yang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Jie Jian"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Lungen Lu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Hui Dong"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Xiaobo Cai"
    }
  ],
  "title": "Endothelial RAP1A attenuates sinusoidal capillarisation and liver fibrosis by inhibiting RAF1-mediated Notch activation",
  "uid": "e0534c38-caff-558b-b908-eca455b5d8bf"
}