Vinores Stanley A, Xiao Wei-Hong, Aslam Sadia, Shen Jikui, Oshima Yuji, Nambu Hiroyuki, Liu Hansheng, Carmeliet Peter, Campochiaro Peter A
Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9289, USA.
J Cell Physiol. 2006 Mar;206(3):749-58. doi: 10.1002/jcp.20525.
Retinal neovascularization (NV) and macular edema, resulting from blood-retinal barrier (BRB) breakdown, are major causes of visual loss in ischemic retinopathies. Choroidal NV (CNV) occurs in diseases of the retinal pigmented epithelium/Bruch's membrane complex and is another extremely prevalent cause of visual loss. We used mice in which the hypoxia response element (HRE) is deleted from the vascular endothelial growth factor (vegf) promoter (Vegf(delta/delta) mice) to explore the role of induction of VEGF through the HRE in these disease processes. Compared to wild type (Vegf+/+) mice with oxygen-induced ischemic retinopathy (OIR) in which vegf mRNA levels were increased and prominent retinal NV and BRB breakdown occurred, Vegf(delta/delta) littermates with OIR failed to increase vegf mRNA levels in the retina and had significantly less retinal NV and BRB breakdown, but showed prominent dilation of some superficial retinal vessels. Vegf(+/delta) littermates with ischemic retinopathy developed comparable retinal NV to Vegf+/+ mice, exhibited intermediate levels of BRB breakdown, and did not show vasodilation. In a mouse model of CNV, due to laser-induced rupture of Bruch's membrane, the area of CNV at Bruch's membrane rupture sites was more than tenfold greater in Vegf+/+ mice than in Vegf(delta/delta) littermates. In contrast to these dramatic differences in pathologic ocular NV, Vegf(delta/delta) mice showed subtle differences in retinal vascular development compared to Vegf+/+ mice; it was slightly delayed, but otherwise normal. These data suggest that induction of VEGF through the HRE in its promoter is critical for retinal and CNV, but not for retinal vascular development.
血视网膜屏障（BRB）破坏导致的视网膜新生血管（NV）和黄斑水肿是缺血性视网膜病变中视力丧失的主要原因。脉络膜新生血管（CNV）发生于视网膜色素上皮/布鲁赫膜复合体疾病，是另一个极其常见的视力丧失原因。我们使用了在血管内皮生长因子（VEGF）启动子中缺氧反应元件（HRE）被删除的小鼠（Vegf(delta/delta)小鼠），以探究通过HRE诱导VEGF在这些疾病过程中的作用。与野生型（Vegf+/+）小鼠相比，患有氧诱导缺血性视网膜病变（OIR）的野生型小鼠VEGF mRNA水平升高，出现明显的视网膜NV和BRB破坏，而患有OIR的Vegf(delta/delta)同窝小鼠视网膜中VEGF mRNA水平未能升高，视网膜NV和BRB破坏明显减少，但一些视网膜浅表血管出现明显扩张。患有缺血性视网膜病变的Vegf(+/delta)同窝小鼠发生的视网膜NV与Vegf+/+小鼠相当，BRB破坏程度处于中等水平，且未出现血管扩张。在CNV小鼠模型中，由于激光诱导布鲁赫膜破裂，Vegf+/+小鼠布鲁赫膜破裂部位的CNV面积比Vegf(delta/delta)同窝小鼠大十多倍。与病理性眼NV的这些显著差异形成对比的是，与Vegf+/+小鼠相比，Vegf(delta/delta)小鼠在视网膜血管发育方面表现出细微差异；其发育略有延迟，但其他方面正常。这些数据表明，通过其启动子中的HRE诱导VEGF对视网膜和CNV至关重要，但对视网膜血管发育并非如此。
