Abstract
Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X7 participates in the modulation of inflammation, angiogenesis, fibrogenesis and vasoresponsiveness, but the relevant influence in cirrhosis is unknown. Common bile duct-ligated (CBDL) or sham-operated Spraque-Dawley rats received brilliant blue G (BBG, a P2X7 antagonist and food additive) or vehicle from the 15th to 28th day after operations, then hemodynamics, mesenteric angiogenesis, portal-systemic shunting, liver fibrosis, and protein expressions of angiogenic and fibrogenic factors were evaluated. The influence of oxidized ATP (oATP, another P2X7 receptor antagonist) on the collateral vasoresponsiveness to arginine vasopressin (AVP) was also surveyed. BBG decreased superior mesenteric artery (SMA) flow, portal-systemic shunting, mesenteric vascular density, and mesenteric protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), phospho (p)-VEGFR2, platelet-derived growth factor (PDGF), PDGF receptor beta (PDGFRβ), cyclooxygenase (COX)-1, COX-2, and endothelial NO synthase (eNOS) in CBDL rats. BBG also ameliorated liver fibrosis and down-regulated hepatic interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), PDGF, IL-1β, transforming growth factor-beta (TGF-β), p-extracellular-signal-regulated kinases (ERK), and alpha-smooth muscle actin (α-SMA) expressions in CBDL rats. The collateral vasocontractility to AVP was enhanced by oATP. oATP down-regulated eNOS, inducible NOS (iNOS), VEGF, Akt, p-Akt, and nuclear factor-kappa B (NF-κB) expressions in splenorenal shunt, the most prominent intra-abdominal collateral vessel in rodents. P2X7 antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X7 blockade may be a feasible strategy to control cirrhosis and complications.
Highlights
Liver inflammation is usually followed by fibrogenesis, cirrhosis and complications from increased intrahepatic resistance and portal hypertension
A salient feature of portal hypertension is the formation of an extensive network of portalsystemic collateral vessels including the gastroesophageal varices, which may rupture with a high mortality rate [27]
Brilliant blue G (BBG), a P2X7 receptor antagonist as an “edible” blue dye significantly ameliorated the severity of portal-systemic shunting and mesenteric angiogenesis in Common bile duct-ligated (CBDL) rats, implying that P2X7 inhibition can be a candidate to control the complications associated with angiogenesis in cirrhosis
Summary
Liver inflammation is usually followed by fibrogenesis, cirrhosis and complications from increased intrahepatic resistance and portal hypertension. Liver cirrhosis with portal hypertension is characterized by systemic and splanchnic vasodilatory substances release, especially nitric oxide (NO) and prostacyclin [3], which lead to hyperdynamic circulatory status, and further increased mesenteric blood flow and portal inflow. We have demonstrated that NO and/or prostacyclin inhibition enhanced the collateral vasoresponsiveness to arginine vasopressin (AVP) in portal hypertensive rats [4], suggesting their role in this situation. Inhibition of VEGFR2 attenuated hyperdynamic splanchnic circulation and collaterals in portal hypertensive rats, suggesting the beneficial effects of antiangiogenesis in ameliorating this pathological condition [6]
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