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(Circulation Research. 2003;93:438.)
© 2003 American Heart Association, Inc.

Cellular Biology

Angiotensin II Type 2 Receptor Inhibits Vascular Endothelial Growth Factor–Induced Migration and In Vitro Tube Formation of Human Endothelial Cells

Ralf Benndorf, Rainer H. Böger, Süleyman Ergün, Anna Steenpass, Thomas Wieland

From the Institut für Experimentelle und Klinische Pharmakologie (R.B., R.H.B., A.S.), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Institut für Anatomie (S.E.), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; and Institut für Pharmakologie und Toxikologie (T.W.), Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany.

Correspondence to Dr Ralf Benndorf, Institut für Experimentelle und Klinische, Pharmakologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail benndorf{at}uke.uni-hamburg.de

Endothelial cell migration and tube formation in response to vascular endothelial growth factor (VEGF) play an important role in the process of angiogenesis. Recent data indicate that angiotensin type 2 (AT₂) receptor stimulation is antiangiogenic. Therefore, we studied the effect of angiotensin II (Ang II) on VEGF-induced migration and in vitro tube formation of human endothelial cells. Ang II inhibited VEGF-induced migration of EA.hy926 cells, human coronary artery (HCA) and human dermal microvascular (HDM) endothelial cells (ECs) as well as tube formation by HDMECs. The AT₂ receptor antagonist PD123,319 but not the AT₁ receptor antagonist losartan blocked the inhibitory effect of Ang II. The inhibitory effect of Ang II on VEGF-induced migration of endothelial cells was mimicked by the specific AT₂ receptor agonist CGP-42112A. The phosphorylation of Akt and its downstream effector endothelial NO synthase (eNOS) is pivotal to VEGF-induced angiogenesis. We therefore investigated the effect of Ang II on VEGF-induced Akt and eNOS phosphorylation. Ang II diminished the VEGF-induced phosphorylation of Akt and eNOS in endothelial cells, whereas the autophosphorylation of VEGF receptors was unaffected. CGP-42112A again mimicked and PD123,319 but not losartan blocked the inhibitory effect of Ang II. Treatment of endothelial cells with pertussis toxin (PTX) totally abolished the AT₂ receptor–mediated inhibition of VEGF-induced endothelial cell migration and blocked the inhibition of Akt and eNOS phosphorylation. In conclusion, this study indicates that AT₂ receptor stimulation inhibits VEGF-induced endothelial cell migration and tube formation via activation of a PTX-sensitive G protein. These findings may explain the reported antiangiogenic properties of the AT₂ receptor.

Key Words: angiogenesis • migration • angiotensin II • AT₂ receptor

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