Stimulation of neovascularization by the anti-angiogenic factor PEDF
Stimulation of neovascularization by the anti-angiogenic factor PEDF
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DOI：
10.1167/iovs.04-0172
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发表时间：
2004-12-01
影响因子：
4.4
通讯作者：
Ferguson, TA
中科院分区：
文献类型：
--
作者：
Apte, RS;Barreiro, RA;Ferguson, TA
目的。观察色素上皮衍生生长因子(PEDF)对激光诱导的脉络膜新生血管(CNV)的影响。方法：成年C57BL/6小鼠麻醉后，用氪红激光(614 nm，50微米，0.05秒，200 mW)在眼底各象限放置4个激光斑点。动物接受不同剂量的PEDF治疗，皮下植入微渗泵。激光治疗7天后，用3%FITC高分子右旋糖苷溶液灌流小鼠，摘除眼球，共聚焦显微镜下观察新生血管形成情况。数据记录为新生血管复合体的体积。测定PEDF对内皮细胞迁移、合成基底膜血管形成和血管内皮生长因子产生的影响。结果：接受低剂量PEDF(90µg/mL)的小鼠CNV面积显著减少。高剂量(360µg/mL)的PEDF可显著增加CNV，而中剂量(180µg/mL)的PEDF则无明显作用。低剂量(0.5-5µg/mL)的PEDF可抑制内皮细胞迁移和血管形成。高剂量的PEDF(25-50µg/mL)刺激内皮细胞迁移，促进体外血管形成，并刺激内皮细胞产生血管内皮细胞生长因子。中和抗血管内皮生长因子抗体可完全逆转大剂量PEDF对活体CNV的刺激作用。结论PEDF对CNV的刺激作用与内皮细胞功能相反。虽然低剂量是抑制作用，但高剂量可以促进新生血管的发育。这些结果表明，PEDF对新生血管的影响比最初认为的要复杂得多，在考虑PEDF治疗时应谨慎行事。
PURPOSE. Examine the effect of (pigment epithelium-derived growth factor; PEDF) on laser-induced choroidal neovascularization (CNV).METHODS. Adult C57Bl/6 mice were anesthetized and four laser spots were placed in each quadrant of the fundus with a krypton red laser (614 nm, 50 mum, 0.05 second, 200 mW). Animals were treated with various doses of PEDF administered with miniosmotic pumps implanted subcutaneously. Seven days after laser treatment, mice were perfused with 3% FITC high-molecular-weight dextran, the eyes enucleated, and neovascularization analyzed by confocal microscopy. Data were recorded as the volume of the neovascular complex. The effect of PEDF on endothelial cell migration, vascular tube formation in synthetic basement membrane, and VEGF production was also determined.RESULTS. Mice receiving a lower dose of PEDF (90 mug/mL) had significantly decreased areas of CNV. A high dose of PEDF ( 360 mug/mL) significantly increased CNV, whereas an intermediate dose (180 mug/mL) of PEDF had no effect. PEDF inhibited endothelial cell migration and vascular tube formation at lower doses (0.5-5 mug/mL). High doses of PEDF (25-50 mug/mL) stimulated endothelial cell migration, enhanced vascular tube formation in vitro, and stimulated VEGF production from endothelial cells. Neutralizing anti-VEGF antibody completely reversed the stimulatory effects of high doses of PEDF on CNV in vivo.CONCLUSIONS. PEDF demonstrates opposing effects on CNV and endothelial cell function. Whereas low doses are inhibitory, high doses can augment the development of the neovasculature. These results suggest that the effects of PEDF on neovascularization are more complex than originally believed and that caution should be exercised when PEDF therapies are considered.