Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin.
The serine/threonine protein kinase Akt is involved in a variety of cellular processes including cell proliferation, survival, metabolism and gene expression. It is essential in vascular endothelial growth factor (VEGF)-mediated angiogenesis; however, it is not known how Akt regulates the migration of endothelial cells, a crucial process for vessel sprouting, branching and the formation of networks during angiogenesis. Here we report that Akt-mediated phosphorylation of Girdin, an actin-binding protein, promotes VEGF-dependent migration of endothelial cells and tube formation by these cells. We found that exogenously delivered adenovirus harbouring Girdin short interfering RNA in Matrigel embedded in mice, markedly inhibited VEGF-mediated angiogenesis. Targeted disruption of the Girdin gene in mice impaired vessel remodelling in the retina and angiogenesis from aortic rings, whereas Girdin was dispensable for embryonic vasculogenesis. These findings demonstrate that the Akt/Girdin signalling pathway is essential in VEGF-mediated postneonatal angiogenesis.
Kitamura
Tomoya
T
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Asai
Naoya
N
Enomoto
Atsushi
A
Maeda
Kengo
K
Kato
Takuya
T
Ishida
Maki
M
Jiang
Ping
P
Watanabe
Takashi
T
Usukura
Jiro
J
Kondo
Takahisa
T
Costantini
Frank
F
Murohara
Toyoaki
T
Takahashi
Masahide
M
D000818:Animals; D001011:Aorta / Q000378:metabolism; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D008840:Microfilament Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; C502451:CCDC88A protein, human; C527550:Ccdc88a protein, mouse