title: Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis.
abstract: Certain pathological changes, including angiogenesis, actively contribute to the pathogenesis of splenomegaly in portal hypertension (PH), although the detailed molecular and cellular mechanisms remain elusive. In this study, we demonstrated that endothelial Grb-2-associated binder 1 (Gab1) plays a negative role in PH-associated splenomegaly independent of angiogenesis. PH, which was induced by partial portal vein ligation, significantly enhanced Gab1 expression in endothelial cells in a time-dependent manner. Compared with controls, endothelium-specific Gab1 knockout (EGKO) mice exhibited a significant increase in spleen size while their PH levels remained similar. Pathological analysis indicated that EGKO mice developed more severe hyperactive white pulp and fibrosis in the enlarged spleen but less angiogenesis in both the spleen and mesenteric tissues. Mechanistic studies showed that the phosphorylation of endothelial nitric oxide synthase (eNOS) in EGKO mice was significantly lower than in controls. In addition, the dysregulation of fibrosis and inflammation-related transcription factors [e.g., Krüppel-like factor (KLF) 2 and KLF5] and the upregulation of cytokine genes (e.g., TNF-α and IL-6) were observed in EGKO mice. We thus propose that endothelial Gab1 mediates multiple pathways in inhibition of the pathogenesis of splenomegaly in PH via prevention of endothelial dysfunction and overproduction of proinflammatory/profibrotic cytokines.
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China;
authors.forename: Beibei
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China;
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China;
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Huo
authors.affiliation: People's Hospital, Peking University, Beijing, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Physiology and Medicine, Jobu University, Takasaki, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China; jincailuo@pku.edu.cn.
authors.forename: Jincai
authors.identifier: http://orcid.org/0000-0002-9614-8776
authors.initials: J
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006975:Hypertension, Portal / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D013163:Splenomegaly / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C490897:Gab1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D010750:Phosphoproteins; D052250:Nitric Oxide Synthase Type III
keywords: Gab1; portal hypertension; splenomegaly