Published online before print July 24, 2003, doi: 10.1161/01.RES.0000088358.99466.04
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Submitted on November 13, 2002
Revised on July 2, 2003
Accepted on July 16, 2003
Angiotensin II Type 2 Receptor Inhibits Vascular Endothelial Growth Factor-Induced Migration and In Vitro Tube Formation of Human Endothelial Cells
Ralf Benndorf *;
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.
* To whom correspondence should be addressed. 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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