Published Online
on March 24, 2003

A more recent version of this article appeared on May 1, 2003

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Submitted on December 18, 2002
Revised on January 13, 2003

Transactivation of KDR/Flk-1 by the B2 Receptor Induces Tube Formation in Human Coronary Endothelial Cells

Shin-ichiro Miura^*; Yoshino Matsuo; and Keijiro Saku

From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.

^* To whom correspondence should be addressed. E-mail: miuras{at}cis.fukuoka-u.ac.jp.

Abstract--Endothelial cells (ECs) are the critical cellular element responsible for postnatal angiogenesis. Vascular endothelial growth factor (VEGF) stimulates angiogenesis via the activation of kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/Flk-1) in ECs. In addition, transactivation of KDR/Flk-1 by the bradykinin (BK) B2 receptor induces the activation of endothelial nitric oxide synthase (eNOS). These findings indicate that the precise role of BK in angiogenesis is likely to be more complex than initially thought, and it questions the importance of BK in angiogenic processes. Therefore, we examined whether transactivation by BK induced tube formation. We developed an in vitro model of human coronary artery EC (HCEC) tube formation on a matrix gel. We demonstrated that BK dose-dependently induced tube formation. Although a lower concentration of BK and VEGF did not separately induce tube formation, the formation was induced by a combination of lower concentrations of BK and VEGF, suggesting that VEGF and BK had a synergistic effect. The effect was blocked by a B2 receptor antagonist (HOE140) and specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NOS. In addition, BK induced tyrosine phosphorylation of the KDR/Flk-1 receptor, as did VEGF itself. The transactivation was also blocked by HOE140 and Tki. Our results showed that, in HCECs, stimulation of the B2 receptor leads to the transactivation of KDR/Flk-1, as well as to eNOS activation, which induces tube formation. To our knowledge, this is a novel mechanism in which transactivation of KDR/Flk-1 by a G protein-coupled receptor, B2 receptor, may be a potent signal for tube formation.

Key words: endothelium • endothelial growth factors • kinase • receptors, bradykinin • nitric oxide

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