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1 Ophthalmology, Seoul National University College of Medicine, 28 Yondon-Dong Chongno-Gu, Seoul, 110-744, Korea, Republic of; Department of Ophthalmology, Angiogenesis and Laser Laboratories, Retina Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
2 Department of Ophthalmology, Berman Gund Laboratory for the Study of Retinal Degenerations, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
3 Department of Ophthalmology, Angiogenesis and Laser Laboratories, Retina Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
4 Department of Ophthalmology, Howe Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
5 Department of Ophthalmology, Ocular Molecular Genetics Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: ivana_kim{at}meei.harvard.edu.
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Abstract |
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Purpose: Aging-related degradation of the elastic lamina in Bruch’s membrane may have a permissive effect on the growth of choroidal neovascularization (CNV). This study investigated the influence of defective elastic fiber maintenance in development of laser-induced CNV. Methods: A mouse lacking lysyl oxidase-like 1 (LOXL1), an enzyme essential for elastin polymerization, was studied. The morphological characteristics of the elastic lamina within Bruch's membrane were examined in mutant and wild-type (WT) eyes. Laser-induced CNV was evaluated by fluorescein angiography and choroidal flat mounts. Immunohistochemistry for elastin was performed on the CNV lesions, and vascular endothelial growth factor (VEGF) levels were determined by ELISA. Soluble elastin and matrix metalloproteinase (MMPs) levels were also analyzed by immunoblotting. Results: The elastic lamina of Bruch's membrane in the LOXL1-deficient mice was fragmented and less continuous compared to the WT controls. The mutant mice showed increased levels of soluble elastin peptides and reduced elastin polymer deposition in neovascular membranes. Mutant mice developed significantly larger CNV with greater leakage on fluorescein angiography. VEGF levels in the RPE/choroid were higher in the knock-out mice on day 7 and 14 after laser (P < .05). MT1-MMP (MMP14) was also elevated after laser in the LOXL1 mutant eyes compared to the WT controls. Conclusions: These results show that a systemic defect in elastic fiber deposition affects Bruch's membrane integrity and leads to more aggressive CNV growth. The latter may be partially mediated by abnormal signaling from the accumulation of soluble elastin peptides.
Key Words: age-related macular degeneration, angiogenesis, basement membrane, knockout animals
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