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(Circulation Research. 2008;103:261.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Vascular Endothelial Growth Factor Receptor-1 Regulates Postnatal Angiogenesis Through Inhibition of the Excessive Activation of Akt

Jun-ichiro Nishi^*, Tohru Minamino^*, Hideyuki Miyauchi, Aika Nojima, Kaoru Tateno, Sho Okada, Masayuki Orimo, Junji Moriya, Guo-Hua Fong, Kenji Sunagawa, Masabumi Shibuya, Issei Komuro

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., K.S.), 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.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. 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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