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.