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Originally published In Press as doi:10.1167/iovs.07-1508 on February 22, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:2599-2605.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1508
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Increased Choroidal Neovascularization following Laser Induction in Mice Lacking Lysyl Oxidase-like 1

Hyeong Gon Yu,1,2 Xiaoqing Liu,3 Szilard Kiss,1 Edward Connolly,1 Evangelos S. Gragoudas,1 Norman A. Michaud,4 Oleg V. Bulgakov,3 Michael Adamian,3 Margaret M. DeAngelis,5 Joan W. Miller,1 Tiansen Li,3 and Ivana K. Kim1

1From the Angiogenesis Laboratory and Laser Laboratory, Retina Research Institute, the 3Berman-Gund Laboratory for the Study of Retinal Degenerations, the 4Howe Laboratory, and the 5Ocular Molecular Genetics Laboratory, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; and the 2Department of Ophthalmology, Seoul National University of College Medicine, Seoul, Korea.

PURPOSE. Age-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 the development of laser-induced CNV.

METHODS. A mouse lacking lysyl oxidase-like (LOXL)-1, an enzyme essential for elastin polymerization, was studied. The morphologic 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 than in the WT controls. The mutant mice showed increased levels of soluble elastin peptides and reduced elastin polymer deposition in neovascular membranes. Significantly larger CNV with greater leakage on fluorescein angiography developed in mutant mice. VEGF levels in the RPE/choroid were higher in the knockout mice on days 7 and 14 after laser (P < 0.05). 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.






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