Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium
Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium
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DOI：
10.1016/s0002-9440(10)64063-1
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发表时间：
2001-03-01
影响因子：
6
通讯作者：
D'Amato, RJ
中科院分区：
文献类型：
--
作者：
Schwesinger, C;Yee, C;D'Amato, RJ
老年性黄斑变性的脉络膜新生血管是老年高加索人视力丧失的常见和难以治疗的原因。这种脉络膜新生血管与血管内皮生长因子(VEGF)的表达有关。在目前的动物模型中，脉络膜新生血管是通过在视网膜下注射生长因子或编码生长因子的载体如血管内皮生长因子，或通过激光治疗破坏Bruchs膜/视网膜色素上皮复合体来诱导的。我们希望建立一种转基因的老年性黄斑变性小鼠模型，在该模型中，视网膜色素上皮过表达的血管内皮生长因子可诱导脉络膜新生血管。将组织特异性小鼠视网膜色素上皮启动子(RPE65启动子)与小鼠血管内皮细胞生长因子(164)基因与兔β-珠蛋白-3‘非编码区连接，构建成含兔β-珠蛋白-3’非编码区的重组载体。转基因mRNA在各月龄大鼠视网膜色素上皮中均有表达，4月龄达高峰。视网膜色素上皮和脉络膜中的VEGF蛋白表达均增强。血管内粘附性白细胞增多，血管渗漏增多。组织病理学显示脉络膜内新生血管不能穿透完整的Bruch膜。这些结果支持这样的假设，即需要对Bruch膜的完整性进行额外的侮辱才能诱导脉络膜血管生长到视网膜下空间，就像在老年性黄斑变性中所看到的那样。这一模型可能有助于筛选脉络膜血管生长的抑制物。
Choroidal neovascularization in age-related macular degeneration is a frequent and poorly treatable cause of vision loss in elderly Caucasians. This choroidal neovascularization has been associated with the expression of vascular endothelial growth factor (VEGF). In current animal models choroidal neovascularization is induced by subretinal injection of growth factors or vectors encoding growth factors such as VEGF, or by disruption of the Bruch's membrane/retinal pigment epithelium complex with laser treatment. We wished to establish a transgenic murine model of age-related macular degeneration, in which the overexpression of VEGF by the retinal pigment epithelium induces choroidal neovascularization. A construct consisting of a tissue-specific murine retinal pigment epithelium promoter (RPE65 promoter) coupled to murine VEGF(164) cDNA with a rabbit beta -globin-3' UTR was introduced into the genome of albino mice. Transgene mRNA was expressed in the retinal pigment epithelium at all ages peaking at 4 months. The expression of VEGF protein was increased in both the retinal pigment epithelium and choroid. An increase of intravascular adherent leukocytes and vessel leakage was observed. Histopathology revealed intrachoroidal neovascularization that did not penetrate through an intact Bruch's membrane. These results support the hypothesis that additional insults to the integrity of Bruch's membrane are required to induce growth of choroidal vessels into the subretinal space as seen in age-related macular degeneration. This model may be useful to screen for inhibitors of choroidal vessel growth.