Increased choroidal Neovascularization following laser induction in mice lacking lysyl oxidase-like 1
Increased choroidal Neovascularization following laser induction in mice lacking lysyl oxidase-like 1
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DOI：
10.1167/iovs.07-1508
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Kim, Ivana K.
中科院分区：
文献类型：
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作者：
Yu, Hyeong Gon;Liu, Xiaoqing;Kim, Ivana K.
目的.脉络膜新生血管（CNV）的生长可能与Bruch膜弹性膜的降解有关。本研究调查的影响，有缺陷的弹性纤维的维护在发展中的激光诱导CNV。研究了缺乏赖氨酰氧化酶样（LOXL）-1（弹性蛋白聚合所必需的酶）的小鼠。在突变体和野生型（WT）的眼睛内的弹性膜布鲁赫膜的形态学特征进行了检查。通过荧光素血管造影和脉络膜平片评价激光诱导的CNV。对CNV病变进行弹性蛋白免疫组化，并通过ELISA测定血管内皮生长因子（VEGF）水平。可溶性弹性蛋白和基质金属蛋白酶（MMPs）水平也进行了分析，免疫印迹。L0 XL 1缺陷小鼠中的布鲁赫膜的弹性膜是片段化的，并且比WT对照中的连续性更低。突变小鼠显示可溶性弹性蛋白肽水平增加，新生血管膜中弹性蛋白聚合物沉积减少。在突变小鼠中，荧光素血管造影显示CNV显著更大，渗漏更大。VEGF基因敲除小鼠视网膜色素上皮/脉络膜中VEGF水平在激光后第7天和第14天均高于对照组（P < 0.05）。与WT对照组相比，LOXL 1突变眼激光治疗后MT 1-MMP（MMP 14）也升高。这些结果表明，弹性纤维沉积的系统性缺陷影响Bruch膜的完整性，并导致更积极的CNV生长。后者可能部分介导的异常信号从可溶性弹性蛋白肽的积累。
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.