Suppression of renin-angiotensin system attenuates hepatocarcinogenesis via angiogenesis inhibition in rats.

Recent studies have shown that the renin-angiotensin system (RAS) as well as angiogenesis is involved in tumor development. The aim of the present study was to examine the interaction of RAS, angiogenesis and a potent angiogenic factor, namely the vascular endothelial growth factor (VEGF), in the hepatocarcinogenesis process. In a diethylnitrosamine-induced rat hepatocarcinogenesis model, a clinically used angiotensin-converting enzyme inhibitor, perindopril (PE), significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions along with inhibition of neovascularization in the liver. The hepatic expression of VEGF was also attenuated. The degree of angiogenesis correlated well with the development of preneoplastic lesions. Our in vitro study showed that PE significantly suppressed VEGF-induced tubular formation and the migration of endothelial cells (EC), whereas it did not affect the proliferation of EC. These results suggested that RAS plays an important role in hepatocarcinogenesis, at least partly through VEGF-mediated angiogenesis.