Published online before print June 26, 2008, doi: 10.1161/CIRCRESAHA.108.174128
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Submitted on July 3, 2007
Revised on June 11, 2008
Accepted on June 16, 2008
Vascular Endothelial Growth Factor Receptor-1 Regulates Postnatal Angiogenesis Through Inhibition of the Excessive Activation of Akt
Jun-ichiro Nishi ;
From the Department of Cardiovascular Science and Medicine (J.N., T.M., H.M., A.N., K.T., S.O., M.O., J.M., I.K.), Chiba University Graduate School of Medicine, Japan; PRESTO (T.M.), Japan Science and Technology Agency, Saitama, Japan; the Department of Physiology (G.-H.F.), University of Connecticut Health Center, Farmington; the Department of Cardiovascular Medicine (J.N.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and the Department of Molecular Oncology (M.S.), Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Japan.
* To whom correspondence should be addressed. E-mail: komuro-tky{at}umin.ac.jp.
Vascular endothelial growth factor (VEGF) binds both VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2). Activation of VEGFR-2 is thought to play a major role in the regulation of endothelial function by VEGF. Recently, specific ligands for VEGFR-1 have been reported to have beneficial effects when used to treat ischemic diseases. However, the role of VEGFR-1 in angiogenesis is not fully understood. In this study, we showed that VEGFR-1 performs "fine tuning" of VEGF signaling to induce neovascularization. We examined the effects of retroviral vectors expressing a small interference RNA that targeted either the VEGFR-1 gene or the VEGFR-2 gene. Deletion of either VEGFR-1 or VEGFR-2 reduced the ability of endothelial cells to form capillaries. Deletion of VEGFR-1 markedly reduced endothelial cell proliferation and induced premature senescence of endothelial cells. In contrast, deletion of VEGFR-2 significantly impaired endothelial cell survival. When VEGFR-1 expression was blocked, VEGF constitutively activated Akt signals and thus induced endothelial cell senescence via a p53-dependent pathway. VEGFR-1+/- mice exhibited an increase of endothelial Akt activity and showed an impaired neovascularization in response to ischemia, and this impairment was ameliorated in VEGFR-1+/- Akt1+/- mice. These results suggest that VEGFR-1 plays a critical role in the maintenance of endothelial integrity by modulating the VEGF/Akt signaling pathway.
Key words: VEGF • Akt • senescence • p53
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