Lack of netrin-4 modulates pathologic neovascularization in the eye.
Lack of netrin-4 modulates pathologic neovascularization in the eye.
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DOI：
10.1038/srep18828
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发表时间：
2016-01-06
影响因子：
4.6
通讯作者：
Joussen AM
中科院分区：
文献类型：
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作者：
Kociok N;Crespo-Garcia S;Liang Y;Klein SV;Nürnberg C;Reichhart N;Skosyrski S;Moritz E;Maier AK;Brunken WJ;Strauß O;Koch M;Joussen AM
网蛋白是一类具有引导信号功能的基质结合蛋白。Netrin-4在肿瘤发生和新生血管形成中发挥病理作用。为了回答netrin-4是促进血管生成还是抑制血管生成的问题，我们在氧诱导视网膜病变（OIR）和激光诱导脉络膜新生血管（CNV）的nn -4 - / -小鼠中评估了视网膜血管生成，模拟缺氧介导的新生血管和炎症介导的血管生成。发现基底膜蛋白netrin-4定位于成熟的视网膜血管。Netrin-4 mRNA的表达在相对缺氧的情况下增加，并在血管形成结束时恢复到正常水平，而netrin-1 mRNA的表达则没有增加。正常环境下的nn -4−/−小鼠视网膜未见变化。在OIR中，nt -4 - / -小鼠最初表现出更大的无血管区域，并且更快地恢复到血运重建。甘兹菲尔德视网膜电图显示nn -4−/−小鼠视网膜功能恢复较快。神经网络蛋白受体Unc5H2 （Unc-5同源物B，秀丽隐杆线虫）和DCC（在结直肠癌中缺失）在肝细胞和星形胶质细胞中表达。激光诱导的Nnt-4−/−小鼠新生血管与对照组没有差异。我们的研究结果表明，netrin-4作为一种血管生成调节因子在o2依赖性血管稳态中发挥作用，而在正常视网膜发育血管生成或炎症新生血管形成过程中则不太重要。
Netrins are a family of matrix-binding proteins that function as guidance signals. Netrin-4 displays pathologic roles in tumorigenesis and neovascularization. To answer the question whether netrin-4 acts either pro- or anti-angiogenic, angiogenesis in the retina was assessed in Ntn-4−/− mice with oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), mimicking hypoxia-mediated neovascularization and inflammatory mediated angiogenesis. The basement membrane protein netrin-4 was found to be localised to mature retinal blood vessels. Netrin-4, but not netrin-1 mRNA expression, increased in response to relative hypoxia and recovered to normal levels at the end of blood vessel formation. No changes in the retina were found in normoxic Ntn-4−/− mice. In OIR, Ntn-4−/− mice initially displayed larger avascular areas which recovered faster to revascularization. Ganzfeld electroretinography showed faster recovery of retinal function in Ntn-4−/− mice. Expression of netrin receptors, Unc5H2 (Unc-5 homolog B, C. elegans) and DCC (deleted in colorectal carcinoma), was found in Müller cells and astrocytes. Laser-induced neovascularization in Nnt-4−/− mice did not differ to that in the controls. Our results indicate a role for netrin-4 as an angiogenesis modulating factor in O2-dependent vascular homeostasis while being less important during normal retinal developmental angiogenesis or during inflammatory neovascularization.