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E. Cheung, I. B. Lobov, G. Thurston, N. W. Gale, G. D. Yancopoulos, S. J. Wiegand; Genetic Deletion of Notch-Regulated Ankryrin- Repeat Protein (NRARP) Affects Normal Retinal Vascular Development and Neovascularization in the OIR Model in Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):524.
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Notch receptors play crucial roles in regulating the development and differention of numerous tissue. The notch-regulated ankyrin-repeat protein (Nrarp), appears to act as an intracellular negative feedback regulator of Notch signaling in the process of somite formation and CNS development. Recently, it has been shown that the Notch ligand, Delta-like ligand 4 (Dll4) plays an important role in vascular development, by modulating angiogenic sprouting and endothelial cell proliferation in both normal, and pathological conditions [Lobov et al., PNAS 2007, 104(9): 3219-24; Hellstrom et al., Nature 2007, 445(7129):776-80; Noguera-Troise et al., Nature 2006, 444(7122):1032-7]. The purpose of this study was to evaluate the effects of Nrarp gene deletion on normal retinal vascular development, and on vasoobliteration and neovascularization in a murine model of oxygen-induced ischemic retinopathy (OIR).
Mice heterozygous for Nrarp gene deletion were bred to generate litters containing Nrarp null, heterozygous, and wild-type mice. Retinas were collected at P7, flatmounted, and stained with FITC-labeled Griffonia simplicifolia (GS) lectin I. For OIR model, litters were place in a 75% O2 environment at P7 and returned to room air at P12. Retinas were collected at P12 and P17, flatmounted, and stained with GS lectin I and Glial Fibrillary Acidic Protein (GFAP).
In both normal development and the OIR model, Nrarp knockout mice exhibited significant reductions in retinal vessel density compared to wild-type littermates. Moreover, in OIR treated mice, Nrarp null mice showed increased vaso-obliteration at P12, and at P17 exhibited increased pathological neovascularization. Mice heterozygous for Nrarp deletion exhibited an intermediate phenotype. Thus, Nrarp deficiency produced effects opposite to those previously observed following genetic or pharmacological inhibition of the Dll4/Notch signaling: specifically, Nrarp deletion resulted in reduced angiogenic sprouting and capillary density during normal retinal development, while increasing vaso-obliteration and pathological neovascularization in OIR.
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