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T. Suzuki, S.-M. Kwon, Y. Nakagawa, K. Kawai, S. Takaki, T. Asahara; Improvement of Pathological Neovascularization and Astrocyte Abnormalities in a Mouse Model of Oxygen-Induced Retinopathy by Augmenting Bone Marrow-Derived Endothelial Progenitor Cell Recruitment via Lnk Deletion. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5654.
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We have previously reported that the Lnk deletion resulted in improvement of pathological neovascularization in a mouse model of oxygen-induced retinopathy via augmenting bone marrow-derived endothelial progenitor cells (EPCs). In this study we further characterize new mechanisms about improvement of pathological neovascularization via augmenting EPCs, and more recovery of astrocyte abnormalities in Lnk-/- mice.
OIR was induced by 5 days 75% oxygen exposure and then incubation under room air condition (21% oxygen) in postnatal day 7 (P7) C57BL/6J wild type (WT) and Lnk-/- mice. We evaluated the angiogenesis both in WT and Lnk-/- mice, and examined the effects of Lnk gene deletion on EPC population in bone marrow and peripheral blood by FACS analysis,EPC colony-forming assay, and quantitive RT-PCR analysis. Furthermore, we performed transfusion study with isolated GFP+ Sca1+ lineage- cells in OIR mice to examine the homing capacity of bone marrow-derived EPCs. The status of astrocyte was evaluated by glial fibrillary acidic protein (GFAP) immunohistochemistry.
Lnk deletion reduced avascular area, retinal hemorrhage area, and astrocyte abnormal area at P17 by 52%, 60%, and 49% compared with control. Neovascular tufts quantified from wholemounts were reduced by 51%. The number of EPCs both in bone marrow and peripheral blood was increased in Lnk-/- mice, and Lnk-/- EPCs in peripheral blood had more vasculogenic capacity and higher RNA expressions of vessel maturation factors compared with control. In addition, transfused Lnk-/- EPCs had more homing capacity compared with control.
In this study, we showed new EPCs mechanisms for ischemic retinopathy, and demonstrated that Lnk deletion not only improved pathological angiogenesis, but astrocyte abnormalities with EPC contribution. Therefore, inhibition of Lnk expression may provide an effective target for the treatment of retinal neovascular diseases as well as ischemic retinopathy.
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