Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth

Kimiyasu Egami, Toyoaki Murohara, Toshifumi Shimada, Ken Ichiro Sasaki, Satoshi Shintani, Takeshi Sugaya, Masahiro Ishii, Teiji Akagi, Hisao Ikeda, Toyojiro Matsuishi, Tsutomu Imaizumi

Research output: Contribution to journalArticle

265 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)67-75
Number of pages9
JournalJournal of Clinical Investigation
Volume112
Issue number1
DOIs
Publication statusPublished - Jul 2003
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth'. Together they form a unique fingerprint.

  • Cite this

    Egami, K., Murohara, T., Shimada, T., Sasaki, K. I., Shintani, S., Sugaya, T., Ishii, M., Akagi, T., Ikeda, H., Matsuishi, T., & Imaizumi, T. (2003). Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. Journal of Clinical Investigation, 112(1), 67-75. https://doi.org/10.1172/JCI16645