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M.H. Davies, M.R. Powers; MCP–1 Deficient Mice Exhibit a Prolonged Neovascular Response in a Mouse Model of Oxygen–Induced Retinopathy . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4185.
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Purpose: Microglial cells (MC) and macrophages (Mac) have been known to promote angiogenesis, induce apoptosis, as well as perform phagocytic functions suggesting a possible role in retinal injury. We previously reported MC/Mac activation and recruitment to areas of retinal neovascularization and dysplasia following an increase in monocyte chemoattractant protein–1 (MCP–1) expression in a model of oxygen–induced retinopathy. The present study investigates if retinal neovascularization is altered in CCL2–/– (MCP–1) knockout mice, which have reduced ability to recruit and activate MC/Mac to sites of injury. Methods: Postnatal day (P)7 CCL2–/– and congenic C57BL/6 (B6) mice were exposed to 75% oxygen for up to 5 days (P12), and then recovered in room air. Eyes from oxygen–exposed (O2) mice and unexposed controls were obtained at various time points for histopathological studies. Intraretinal blood vessel formation was quantified by immunolabeling vessels with an anti–type IV collagen antibody. Retinopathy was qualitatively assessed in FITC–dextran perfused retinas via fluorescence microscopy. Retinopathy was also assessed by quantifying preretinal neovascular nuclei in P17, P21 (n=8), and P24 (n=4) oxygen–exposed retinas. Results: CCL2–/– and B6 mice revealed similar vascular development under normoxic conditions. Additionally, in oxygen–exposed FITC–dextran perfused P12O2 retinas, the same degree of vaso–obliteration was apparent. By P17O2 the FITC–dextran perfused retinas exhibited prominent neovascular tufts and quantification of preretinal nuclei revealed no significant difference between the CCL2–/– (24.7 ± 5.3) and B6 (24.6 ± 1.3) control mice (P=0.99). However, P21O2 CCL2–/– (30.1 ±6.1) retinas exhibited a significant increase in preretinal neovascular nuclei compared to B6 (6.7 ± 1.1) controls (P=0.025). This prolonged neovascular response continued at P24O2 (P=0.008) with CCL2–/– (9.9 ± 2.2) exhibiting more nuclei than control (1.3 ± 0.28) retinas. Conclusions: Our results demonstrate that the absence of MCP–1 does not alter normal retinal vascular development. Furthermore, CCL2–/– mice, as compared to their congenic controls, develop a similar neovascular response on P17O2. However, by P21O2, the CCL2–/– mice continue to exhibit a large number of preretinal neovascular tufts, suggesting a more severe retinopathy. We speculate the absense of MCP–1 and its effects upon MC/Mac alters vascular tuft regression.
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