Honda M, Sakamoto T, Ishibashi T, Inomata H, Ueno H
Department of Ophthalmology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Gene Ther. 2000 Jun;7(11):978-85. doi: 10.1038/sj.gt.3301203.
Accumulating evidence has shown the importance of vascular endothelial growth factor (VEGF) in chorioretinal angiogenesis. However, whether or not VEGF is indeed critical for the pathogenesis of subretinal neovascularization (SRN) in adulthood, which is a serious complication of age-related macular degeneration, has to be further investigated. We constructed an adenovirus expressing an entire ectodomain of the human VEGF receptor/flt-1 fused to Fc portion of human IgG (Adflt-ExR): this soluble receptor is secreted from Adflt-ExR-transfected cells. We studied the effect of Adflt-ExR on the formation of experimental SRN. Experimental SRN was induced by intense photocoagulation on the retina in pigmented rats and Adflt-ExR was injected into the femoral muscle. The formation of SRN assessed by fluorescein angiography was more significantly inhibited for 7 days in the Adflt-ExR-treated rats than in the control rats who received either an adenovirus vector encoding LacZ gene or balanced salt solution (BSS). The serum concentration of this soluble receptor increased for 7 days and thereafter gradually decreased. An immunohistochemical study disclosed the fibroblast cell proliferation and inflammatory cell infiltration to be reduced in the photocoagulation spot of Adflt-ExR-treated rats. VEGF plays a crucial role in the formation of SRN and VEGF soluble receptor gene transfection can inhibit SRN. This method will contribute to future gene therapy for age-related macular degeneration.
越来越多的证据表明血管内皮生长因子（VEGF）在脉络膜视网膜血管生成中具有重要作用。然而，VEGF对于成年期视网膜下新生血管形成（SRN）的发病机制是否真的至关重要仍有待进一步研究，而SRN是年龄相关性黄斑变性的一种严重并发症。我们构建了一种腺病毒，其表达与人IgG的Fc部分融合的人VEGF受体/flt-1的整个胞外域（Adflt-ExR）：这种可溶性受体从Adflt-ExR转染的细胞中分泌。我们研究了Adflt-ExR对实验性SRN形成的影响。通过对有色大鼠视网膜进行强光凝诱导实验性SRN，并将Adflt-ExR注入股肌。与接受编码LacZ基因的腺病毒载体或平衡盐溶液（BSS）的对照大鼠相比，Adflt-ExR处理的大鼠中，通过荧光素血管造影评估的SRN形成在7天内受到更显著的抑制。这种可溶性受体的血清浓度在7天内升高，此后逐渐下降。免疫组织化学研究显示，Adflt-ExR处理的大鼠光凝部位的成纤维细胞增殖和炎性细胞浸润减少。VEGF在SRN形成中起关键作用，VEGF可溶性受体基因转染可抑制SRN。该方法将有助于未来针对年龄相关性黄斑变性的基因治疗。
