Taurocholate Feeding to Bile Duct Ligated Rats Prevents Caffeic Acid-induced Bile Duct Damage by Changes in Cholangiocyte VEGF Expression

Cholangiocytes are the target cells in cholestatic models of ductal hyperplasia including bile duct ligation (BDL). We have shown that: (i) cholangiocytes express VEGFR-2 and VEGFR-3; (ii) VEGF-A and VEGF-C stimulate cholangiocyte proliferation via an autocrine mechanism; and (iii) chronic administration of VEGF-A prevents cholangiocyte damage induced by hepatic artery ligation. Caffeic acid phenethyl ester (CAPE) induces growth inhibition in different cells. Taurocholic acid (TC) protects cholangiocytes against injury induced by parasympathetic or sympathetic denervation. The aims of this study were to determine if: (i) CAPE induces bile duct damage; and (ii) TIC prevents CAPE-induced bile duct damage by increasing cholangiocyte VEGF expression. Methods: Normal and BDL rats (immediately after surgery) were fed 1% TC or control diet in the absence/presence of daily IP injections of CAPE (10 mg/Kg BW). One week later, we evaluated: (i) cholangiocyte apoptosis, proliferation and ductal mass in liver sections; (ii) functional activity by measuring secretin-stimulated bile and bicarbonate secretion; and (iii) VEGF-A/C and VEGFR-2/R-3 expression in liver sections. In vitro, BDL cholangiocytes were exposed to CAPE (40 mu M) in the absence/presence of TIC (40 mu M) with and without pretreatment with VEGF receptor inhibitors before evaluating cholangiocyte apoptosis and proliferation. Results: Chronic CAPE administration to BDL rats increased cholangiocyte apoptosis and decreased ductal mass. This effect was associated with reduced expression of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3. In vivo, TIC feeding partly prevented CAPE-induced changes in cholangiocyte apoptosis and growth and loss of ductal secretion. The protective effect of TIC was associated with enhanced VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 In vitro, TIC partially prevented CAPE-induced increases in apoptosis and decreases in cholangiocyte proliferation. These changes were reversed by pretreatment with VEGF-receptor inhibitors. Conclusion: Manipulation of cholangiocyte VEGF expression by bile acids may be important in preventing the impairment of cholangiocyte proliferation by exogenous agents. Exp Biol Med 234:462-474, 2009