Abstract
Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3′-diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NFκB, pIκBα protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.
Highlights
Liver cirrhosis with portal hypertension, characterized by increased intrahepatic resistance and splanchnic hyperemia, is considered the end stage of liver diseases
Considering the anti-angiogenesis and anti-fibrotic effects of I3C and DIM, and the easy access to cruciferous vegetables in daily life, this study investigated the influences of I3C and DIM on the development of portal hypertension, liver fibrosis, and the severity of mesenteric angiogenesis and portosystemic collaterals in rats with common bile duct ligation (CBDL)-induced liver cirrhosis
The lower mean arterial pressure (p = 0.017), superior mesenteric arterial resistance (p = 0.001), systemic vascular resistance (p = 0.001), and higher portal pressure (p < 0.001), superior mesenteric artery flow (p = 0.032), cardiac index (p = 0.008), and stroke volume (p < 0.001) in CBDL group indicated that CBDL successfully induced the hemodynamic features of portal hypertension
Summary
Liver cirrhosis with portal hypertension, characterized by increased intrahepatic resistance and splanchnic hyperemia, is considered the end stage of liver diseases. Increased portal inflow to a stiff liver can result in the development of portosystemic collaterals, aiming to divert stagnant blood flow. Recent studies have indicated that angiogenesis participates in the development and aggravation of collaterals and increased portal blood inflow. Vascular endothelial growth factor (VEGF), a potent proangiogenic factor, is overexpressed in splanchnic organs of portal hypertensive animals [2,3]. Splanchnic VEGF receptor 2 (VEGFR2) and endothelial cell marker CD31 are up-regulated in portal hypertensive rats [2]. These findings suggest that anti-angiogenesis may be a new treatment strategy in controlling portal hypertension
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