Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor–deficient (AT1a–/–) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a–/– mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the β-galactosidase gene was inserted into the AT1a gene locus in AT1a–/– mice, the site of β-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a–/– mice, the major site of the β-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a–/– mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo.
Kimiyasu Egami, Toyoaki Murohara, Toshifumi Shimada, Ken-ichiro Sasaki, Satoshi Shintani, Takeshi Sugaya, Masahiro Ishii, Teiji Akagi, Hisao Ikeda, Toyojiro Matsuishi, Tsutomu Imaizumi