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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2673.)
© 2006 American Heart Association, Inc.

Vascular Biology

Negative Regulation of VEGF-Induced Vascular Leakage by Blockade of Angiotensin II Type 1 Receptor

Hideto Sano; Kohei Hosokawa; Hiroyasu Kidoya; Nobuyuki Takakura

From the Department of Stem Cell Biology (H.S., K.H., H.K., N.T.), Cancer Research Institute, Kanazawa University, Japan; and the Department of Signal Transduction (H.K., N.T.), Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. Current address for N.T.: Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Japan.

Correspondence to Nobuyuki Takakura, MD, PhD, Department of Stem Cell Biology, Cancer Research Institute, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-0934 Japan. E-mail ntakaku{at}kenroku.kanazawa-u.ac.jp

Objective— Permeability of blood vessels is essential for tissue homeostasis. However, disorganized hyperpermeability leads to progression of diseases. Vascular endothelial growth factor-A (VEGF) is a key regulator for leakiness of blood vessels and it has been reported that VEGF-mediated hyperpermeability was suppressed by angiopoietin-1 (Ang1). We found that Angiotensin-converting enzyme (ACE) was downregulated in endothelial cells by Ang1. ACE converts angiotensin I to angiotensin II (AII). Here, we studied the relationship between VEGF and AII relative to vascular permeability.

Methods and Results— We showed that VEGF-mediated vascular hyperpermeability was suppressed in mice given AII type 1 receptor (AT1R) blocker (ARB); the effect was also seen in AT1R-deficient mice. In this system, we found that ARB inhibited VEGF-induced gap formation. Furthermore, we ascertained that angioedema induced by overexpression of VEGF decreased noticeably in ARB-treated ischemic mice.

Conclusions— Because ARB suppressed VEGF-induced vascular hyperpermeability, we propose that ARB may be used to minimize the risk of edema in therapeutic angiogenesis using VEGF.

Angiopoietin-1 (Ang1) suppresses VEGF-mediated hyperpermeability. We found that ACE expression in Endothelial cells was negatively or positively regulated by Ang1 or VEGF, respectively, and VEGF-mediated hyperpermeability was suppressed by Angiotensin II type1 receptor blocker (ARB) suggesting availability of ARB for minimizing the risk of edema in therapeutic angiogenesis using VEGF.

Key Words: VEGF • Tie2 • angiotensin-converting enzyme • gene therapy • VE-cadherin