Involvement of Hyaluronan and Its Receptor CD44 with Choroidal Neovascularization
Involvement of Hyaluronan and Its Receptor CD44 with Choroidal Neovascularization
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DOI：
10.1167/iovs.08-3044
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发表时间：
2009-09-01
影响因子：
4.4
通讯作者：
Tsubota, Kazuo
中科院分区：
文献类型：
--
作者：
Mochimaru, Hiroshi;Takahashi, Eri;Tsubota, Kazuo
目的. CD 44是一种细胞表面粘附分子和透明质酸（HA）的受体，透明质酸是主要的细胞外基质成分之一。本研究的目的是阐明HA和CD 44在脉络膜新生血管（CNV）发生中的作用。方法。采用激光光凝法诱导C57 BL/6小鼠或CD 44缺陷小鼠的CNV。激光治疗后3天，通过DNA微阵列和实时RT-PCR分析，检测视网膜色素上皮（RPE）-脉络膜复合体中CD 44和HA合成酶（HAS）-2的mRNA表达。光凝后1周，免疫组化检测HA合成和CD 44表达。对激光诱导CNV的小鼠全身给予HA合成抑制剂4-甲基伞形酮（MU）或抗CD 44中和抗体。光凝后1周通过体积测量分析CNV的反应。在激光诱导损伤后3天，通过实时RT-PCR评估F4/80的巨噬细胞浸润到CNV病变中。CNV的诱导导致CD 44和HAS 2 mRNA表达显著增加。HA和CD 44在CNV病变中呈免疫阳性。与溶剂处理相比，MU的全身应用以剂量依赖性方式显著减弱CNV体积，以及巨噬细胞浸润到病变中。与同种型对照相比，基于抗体的CD 44阻断导致CNV体积显著减少。相反，与野生型小鼠相比，CD 44基因切除显著增加CNV形成以及HA积聚和巨噬细胞浸润。这些结果表明HA及其受体CD 44在CNV的发展中起重要作用。（Invest Ophthalmol维斯科学。2009;50：4410-4415）DOI：10.1167/iovs.08-3044
PURPOSE. CD44 is a cell-surface adhesion molecule and receptor for hyaluronan (HA), one of the major extracellular matrix components. The purpose of the present study was to clarify a role of HA and CD44 in the development of choroidal neovascularization (CNV).METHODS. Laser photocoagulation was used to induce CNV in C57BL/6 mice or CD44-deficient mice. The mRNA expression of CD44 and HA synthase (HAS)-2 in the retinal pigment epithelium (RPE)-choroid complex was evaluated by DNA microarray and real-time RT-PCR analyses 3 days after laser treatment. HA synthesis and CD44 expression were examined by immunohistochemistry 1 week after photocoagulation. Mice with laser-induced CNV were systemically administered the HA synthesis inhibitor 4-methylumbelliferone (MU) or an antiCD44-neutralizing antibody. The response of CNV was analyzed by volumetric measurements 1 week after photocoagulation. Macrophage infiltration into CNV lesions was evaluated by real-time RT-PCR for F4/80 3 days after laser-induced injury.RESULTS. The induction of CNV led to a significant increase in expression of CD44 and HAS2 mRNA. HA and CD44 were immunopositive in the CNV lesions. Compared with vehicle treatment, the systemic application of MU significantly attenuated CNV volume in a dose-dependent fashion, together with macrophage infiltration into the lesions. Consistently, antibody-based blockade of CD44 resulted in a significant reduction of CNV volume, compared with the isotype control. In contrast, genetic ablation of CD44 significantly augmented CNV formation together with HA accumulation and macrophage infiltration, compared with wild-type mice.CONCLUSIONS. These results indicate a significant role of HA and its receptor CD44 in the development of CNV. (Invest Ophthalmol Vis Sci. 2009;50:4410-4415) DOI: 10.1167/iovs.08-3044