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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, 840 Shijo-chu, Kashihara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Yanase
Koji
K
Tsujinoue
Hirohisa
H
Imazu
Hiroo
H
Fukui
Hiroshi
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply*; D002465:Cell Movement; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D008113:Liver Neoplasms / Q000098:blood supply*; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000517:prevention & control; D020913:Perindopril / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020913:Perindopril