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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., Kr\u00fcppel-like factor (KLF) 2 and KLF5] and the upregulation of cytokine genes (e.g., TNF-\u03b1 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.<\/jats:p>","DOI":"10.1152\/ajpgi.00292.2014","type":"journal-article","created":{"date-parts":[[2014,12,12]],"date-time":"2014-12-12T05:33:58Z","timestamp":1418362438000},"page":"G416-G426","source":"Crossref","is-referenced-by-count":5,"title":["Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis"],"prefix":"10.1152","volume":"308","author":[{"given":"Beibei","family":"Jiang","sequence":"first","affiliation":[{"name":"Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 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