on September 14, 2006
Published online before print September 14, 2006, doi: 10.1161/01.ATV.0000245821.77155.c3
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Submitted on January 12, 2006
Accepted on August 17, 2006
Negative Regulation of VEGF-Induced Vascular Leakage by Blockade of Angiotensin II Type 1 Receptor
Hideto Sano ;
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.
* To whom correspondence should be addressed. 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.
Key words: VEGF • Tie2 • angiotensin-converting enzyme • gene therapy • VE-cadherin
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