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T. Suzuki, S. Kwon, Y. Nakagawa, K. Kawai, S. Takaki, T. Asahara; Enhancement of Physiologic Retinal Angiogenesis in Lnk–Deficient Mice With Oxygen–Induced Retinopathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1416.
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© ARVO (1962-2015); The Authors (2016-present)
Lnk was proved as an essential inhibitory signal molecule for self–renewality of stem cell by the finding of enhanced hematopoietic reconstitution in Lnk–deficient mice. Lineage negative hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial progenitor cells (EPCs) capable of forming blood vessels, and EPCs mobilize from the bone marrow in response to a variety of signaling molecules and can target sites of angiogenesis in ischemic vasculature. In Keystone Meeting 2005 we presented that Lnk adaptor protein regulates EPCs–mediated signal cascade and the deficiency of Lnk gene results in improvement of postnatal neovascularization in hind limb ischemia model. Therefore, we investigated the angiogenic effects of the lack of Lnk signaling on oxygen–induced retinopathy (OIR).
To develop OIR, postnatal day 7 (P7) C57BL/6J wild type (WT) and Lnk–/– mice were exposed to 75% oxygen for 5 days and then returned to room air. Mice were sacrificed pre–oxygen exposure (P7), immediately following the exposure (P12), and 5 days after return to room air (P17). To investigate the influences lacking for Lnk gene, whole mount retinal preparations of different time points (P7, P12, and P17) were immunostained against PECAM–1 (platelet endothelial cell adhesion molecule), GFAP (glial fibrillary acidic protein), and αSMA (α smooth muscle actin). EPCs–enriched HSCs population was compared as a Sca–1+, c–kit+, Lin– (KSL) population on P17 by FACS analysis. Additionally, neovascularization was quantified by counting the number of nuclei located on the vitreous side of the internal limiting membrane.
Flat–mounted retinas from Lnk–/– mice on P17 showed significantly (P < 0.01) fewer avascular area than WT retinas. In addition, there were significantly (P < 0.01) fewer neovascular cell nuclei detected in the P17 Lnk–/– mice compared to WT. The number of KSL population was increased in Lnk–/– mice.
Retinal avascular area was significantly decreased in Lnk–/– mice with OIR, and pathologic neovascularization was prevented in Lnk–/– mice. Therefore, inhibition of Lnk expression may provide an effective target for treatment of retinal neovascular diseases.
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