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: Beibei Jiang, Qiuping Deng, Yingqing Huo, Wei Li, Masabumi Shibuya, Jincai Luo
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 308 Issue 5 Pg. G416-26 (Mar 01 2015) ISSN: 1522-1547 [Electronic] United States
• PMID: 25501549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytokines
• Gab1 protein, mouse
• Kruppel-Like Transcription Factors
• Phosphoproteins
• Nitric Oxide Synthase Type III

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Cytokines (metabolism)
• Endothelium, Vascular (metabolism)
• Hypertension, Portal (metabolism, pathology)
• Kruppel-Like Transcription Factors (metabolism)
• Mice
• Neovascularization, Pathologic
• Nitric Oxide Synthase Type III (metabolism)
• Phosphoproteins (genetics, metabolism)
• Splenomegaly (metabolism, pathology)