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T. ITO, K. Komeima, T. Yasuma, A. Enomoto, N. Asai, M. Takahashi, H. Terasaki; Girdin Phosphorylation at Serine-1416 by Akt/PKB Promotes Postneonatal Angiogenesis and Ischemic Neovascularization in the Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):51.
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The serine/threonine kinase Akt/PKB substrate Girdin regulates vascular endothelial growth factor (VEGF)-mediated angiogenesis (Kitamura T et al. (2008) Nat Cell Biol.). In this study, we sought to determine if Girdin phosphorylation of serine at position 1416 by Akt/PKB is associated with postneonatal angiogenesis or pathological neovascularization induced by ischemia in the retina.
To test the role of Girdin phosphorylation at serine-1416 in vivo, we used knockin mice in which serine-1416 is mutated to alanine. Postneonatal retinal angiogenesis in knockin mice or wild-type (WT) mice was evaluated at postnatal day 7 (P7) and P10 using confocal microscopy of whole-mounted retinas. Ischemic retinal neovascularization was induced using well-described mouse model of oxygen-induced retinopathy (OIR). Briefly, P7 mice and their nursing dam were exposed to hyperoxia (80% O2) for 5 days and returned to room air at P12. Retinal neovascularization of knockin mice or WT mice was quantified at P17 using confocal microscopy of retinal flatmounts.
Postneonatal vascular development in the retina of knockin mice was significantly slower than that of WT mice. The ratios of vascular area to whole retinal area in knockin mice and WT mice at P7 were 66.7% and 88.4% respectively (p<1.0x10-6), and those at P10 were 97.7% and 99.8% respectively (p<1.0x10-6). Pathological retinal neovascularization by OIR in knockin mice was significantly reduced by 62.6% comparing to WT mice (p<1.0x10-16).
These data demonstrate that phosphorylation of serine at position 1416 in Girdin by Akt/PkB promote postneonatal angiogenesis and pathological neovascularization in the retina, and that inhibition of Girdin phosphorylation by Akt/PKB may reduce pathological retinal neovascularization in patients with ischemic retinal diseases such as retinal vein occlusion, retinopathy of prematurity and diabetic retinopathy.
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