Suppression of the renin-angiotensin system attenuates vascular endothelial growth factor-mediated tumor development and angiogenesis in murine hepatocellular carcinoma cells

Angiotensin-II (AT-II), which is produced mainly by the renin-angiotensin system (RAS), has been shown to stimulate neovascularization. AT-II induces vascular endothelial growth factor (VEGF), which plays a pivotal role in tumor angiogenesis. The role of AT-II, however, in VEGF-mediated tumor development has not yet been elucidated. We examined the effect of RAS inhibition by angiotensin-I converting enzyme (ACE) inhibitor on VEGF-mediated tumor development and angiogenesis in a murine experimental model using a retroviral tetracycline-regulated (Retro-Tet) gene expression system. This system allows VEGF gene expression to be manipulated in vivo by providing tetracycline in the drinking water. In an allograft study, the ACE inhibitor, perindopril (PE) significantly attenuated VEGF-mediated tumor development accompanying the suppression of neovascularization in the tumor at a clinically comparable low dose. In vitro study showed that perindoprilat, which is an active form of PE, inhibited VEGF-induced endothelial cell migration. These results suggested that RAS played an important role in VEGF-mediated tumor development and angiogenesis.