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J.A. Fowler, J.M. Barnett, X.Q. Werdich, R. Yang, J.S. Penn; Matrix Metalloproteinase–2 and –9 Knockout Mice Are Resistant to Oxygen–induced Retinopathy . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3257.
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Purpose: Matrix metalloproteinase (MMP)–2 and –9 are members of the gelatinase family, which are strongly implicated in basement membrane degradation, a necessary step in the angiogenesis cascade. Pharmacologic inhibitors that influence MMP activity often result in broad nonspecific effects. By using MMP knockout mice to investigate oxygen–induced retinopathy (OIR), it is possible to assess specific roles of individual MMPs in angiogenesis. Methods: Litters of mice from each group, C57BL/6 wild type (WT), MMP2–/–, and MMP9–/– were exposed to 75% oxygen for a period of 5 days beginning on postnatal day 7 (P7). Mice were sacrificed pre–oxygen exposure (P7), immediately following exposure (P12), and 7 days after removal from oxygen treatment (P19). Some eyes from mice of each genotype and time point (P7, P12, and P19) were prepared for flat–mount histochemical staining using adenosine diphosphatase (ADPase) stain to show avascular area and pathology. Additionally, 5 µm–thick transverse meridianal retinal sections were made from eyes of each genotype at P19. These were stained with haematoxylin and eosin (H&E) and assessed by counting nuclei within the vitreous cavity in order to show neovascularization. Results: Flat–mounted retinas from MMP–2 and –9 knockout mice on P19 showed significantly less avascular area than WT retinas. MMP–2 and –9 knockout mice demonstrated resistance to OIR seen after H&E staining, displaying 75% (p < 0.001) and 44% (p < 0.001) reduction in formation of retinal neo–vascular tufts, respectively. Conclusions: MMP–2 and –9 play important roles in the pathogenesis of retinopathy in the mouse model of OIR. This confirms previous work demonstrating the significance of MMP–2 in choroidal angiogenesis. MMP activity remains an attractive target for therapeutic intervention in neovascular diseases of the retina.
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