[Transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by the bradykinin B2 receptor induces an angiogenic phenotype in human cultured coronary endothelial cells].
BACKGROUND
Endothelial cells (ECs) are believed to be critical cellular elements responsible for postnatal angiogenesis. Vascular endothelial growth factor (VEGF) stimulates angiogenesis via the activation of KDR/Flk-1 receptor, which is mainly expressed in ECs. Transactivation of KDR/Flk-1 receptor by bradykinin (BK) B2 receptor contributes to the activation of endothelial nitric-oxide (NO) synthase. Therefore, we examined whether transactivation by BK induced angiogenesis.


RESULTS
We developed an in vitro model of human coronary artery ECs (HCECs) tube formation on a matrix gel. We demonstrated that BK dose-dependently induced tube formation. Although a lower concentration of BK did not induce tube formation, the combination of a lower concentration of BK and VEGF did. These effects blocked specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NO synthase. In addition, BK induced the tyrosine phosphorylation of KDR/FlK-1 receptor (transactivation), as did VEGF itself. This transactivation was also blocked by Tki.


CONCLUSIONS
Transactivation of KDR/Flk-1 by BK through B2 receptor is a potent signaling in angiogenic phenotype in HCECs.
Miura
Shin-ichiro
S
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka 814-0142, Japan.
Fujino
Masahiro
M
Tanigawa
Hiroyuki
H
Matsuo
Yoshino
Y
Saku
Keijiro
K
D001920:Bradykinin / Q000494:pharmacology* / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000494:pharmacology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology; D008222:Lymphokines / Q000494:pharmacology / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000502:physiology; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2; D001920:Bradykinin