Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in <i>cd39-</i>null mice

Sun, Xiaofang; Cárdenas, Andrés; Wu, Yan; Enjyoji, Keichi; Robson, Simon C.

doi:10.1152/ajpgi.90703.2008

Cited by 8 publications

(7 citation statements)

References 34 publications

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“…As expected, 7 days after PPVL control mice displayed significant splenomegaly with an increased spleen-to-body (g/g) weight ratio (0.51 Ϯ 0.069) ( Fig. 2C), which is consistent with the published data (22,52). Interestingly, however, EGKO mice developed more pro- nounced splenomegaly (Fig.…”

Section: Endothelial Gab1 Expression Is Increased By Ph In a Timedepesupporting

confidence: 91%

Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis

Jiang

Deng

Huo

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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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.

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Section: Endothelial Gab1 Expression Is Increased By Ph In a Timedepesupporting

confidence: 91%

Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis

Jiang

Deng

Huo

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…There are multiple examples showing that application of inhibitors such as the nucleotide analogue ARL 67156 potentiate nucleotide-mediated neurotransmission [170][171][172][173]. Deletion of NTPDase1 in mice revealed a key role of this enzyme in the prevention of thrombosis [41,42], in purine signaling in angiogenesis [174], vascular permeability [175,176], vascular relaxation [49], in the control of macrophage function [177], or also in promoting tumor growth [178]. Accordingly, transgenic mice expressing human NTPDase1 exhibited impaired platelet aggregation and were protected from thrombosis in a transplantation setting [179].…”

Section: Downstream Signaling Nucleotidesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

878

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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“…Using pharmacological and genetic approaches, a number of studies have demonstrated that extracellular ATP signaling, mainly through P2X1 receptor activation, modulates adrenergic-mediated control of vascular tone in both rat hepatic artery and portal vein systems (47–49). Also, it has been recently shown that ATP stimulation increases portal vein pressure in Cd39 −/− mice upon administration of nitric oxide (NO) inhibitor L-NG-Nitroarginine, suggesting a P2X-dependent vasoconstrictive effect, in absence of P2Y-mediated NO release (50). …”

Section: Modulation Of Liver Functions By P2x Receptorsmentioning

confidence: 99%

Role of purinergic P2X receptors in the control of liver homeostasis

Fausther

Gonzalès

Dranoff

2012

WIREs Membr Transp Signal

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It is now accepted that extracellular ATP and other nucleotides are potent signaling molecules, akin to neurotransmitters, hormones and lipid mediators. In the liver, several clues support a significant role for extracellular ATP-induced signaling pathways in the control of tissue homeostasis. First, ATP and other nucleotides are physiologically detected in extracellular fluids within the liver, including sinusoidal blood and intraductular bile, in various mammalian species including human and rodents. Moreover, finely tuned mechanisms of ATP release by different liver cell types have been described, under physiological cellular changes. In addition, most hepatic cells constitutively express, at the membrane level, several ATP-metabolizing ectoenzymes and ATP-sensitive receptors that modulate and transduce these mediator signals respectively. Finally, hepatic cells also express numerous membrane transporters that actively contribute to purinergic salvage pathways. Once released in the extracellular medium, unmetabolised ATP molecules can bind to purinergic P2X and P2Y receptors, and subsequently trigger various intracellular signal transduction pathways collectively referred to as purinergic signaling. In the liver, purinergic signaling has been shown to regulate key basic cellular functions, such as glucose/lipid metabolism, protein synthesis and ionic secretion, and homeostatic processes, such as cell cycle, inflammatory response and immunity. Whilst the functional relevance of P2Y receptors in liver physiology has been well documented, limited information is available regarding the potential role of hepatic P2X receptors in the modulation of liver homeostasis.

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Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in cd39-null mice

Abstract: Sun X, Cá rdenas A, Wu Y, Enjyoji K, Robson SC. Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in cd39-null mice.

Cited by 8 publications

References 34 publications

Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis

Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis

Cellular function and molecular structure of ecto-nucleotidases

Role of purinergic P2X receptors in the control of liver homeostasis

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