Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia
Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia
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DOI：
10.1161/01.res.0000147365.86159.f5
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发表时间：
2004-10-29
影响因子：
20.1
通讯作者：
Ahmed, A
中科院分区：
文献类型：
--
作者：
Ahmad, S;Ahmed, A
子痫前期是一种血清血管内皮生长因子及其可溶性受体-1(sVEGFR-1，又称sFlt-1)水平升高的炎症性疾病。我们推测，由于高水平的sVEGFR-1导致胎盘血管生成受损，在子痫前期中，血管内皮生长因子和胎盘生长因子(PlGF)调节失调。对先兆子痫胎盘绒毛组织培养上清液的分析显示，sVEGFR-1的表达是正常妊娠的四倍，这表明体外培养的绒毛组织保持着反映长期胎儿编程的低氧记忆。与正常妊娠相比，子痫前期患者外植体释放的VEGF/sVEGFR-1和PlGF/sVEGFR-1的相对比例分别降低了53%和70%。与正常组织相比，暴露于低氧环境下的正常绒毛外植体增加了血管内皮生长因子受体-1的释放(P<；0.001)，肿瘤坏死因子-α的刺激也是如此(P<；来自正常绒毛外植体的条件培养液(CM)诱导内皮细胞迁移和体外管形成，这两种作用都被外源血管内皮生长因子受体-1预先孵育减弱(P<；0.001)。相反，与正常CM相比，经先兆子痫CM处理的内皮细胞血管生成显著减少(P<；0.001)，外源性血管内皮生长因子受体-1的加入不会进一步减少血管生成，这表明可溶性受体饱和。免疫沉淀法去除子痫前期CM中的sVEGFR-1后，迁移(P<；0.001)和管子形成(P<；0.001)显著恢复到与正常CM相当的水平，表明子痫前期患者sVEGFR-1水平升高对血管生成有抑制作用。我们的发现证实了先兆子痫患者血管内皮生长因子/平台生长因子轴的失调，并为其治疗提供了一种全新的治疗方法。
Preeclampsia is an inflammatory disorder in which serum levels of vascular endothelial growth factor ( VEGF) and its soluble receptor-1 (sVEGFR-1, also known as sFlt-1) are elevated. We hypothesize that VEGF and placenta growth factor (PlGF) are dysregulated in preeclampsia due to high levels of sVEGFR-1, which leads to impaired placental angiogenesis. Analysis of supernatants taken from preeclamptic placental villous explants showed a four-fold increase in sVEGFR-1 than normal pregnancies, suggesting that villous explants in vitro retain a hypoxia memory reflecting long-term fetal programming. The relative ratios of VEGF to sVEGFR-1 and PlGF to sVEGFR-1 released from explants decreased by 53% and 70%, respectively, in preeclampsia compared with normal pregnancies. Exposure of normal villous explants to hypoxia increased sVEGFR-1 release compared with tissue normoxia (P < 0.001), as did stimulation with tumor necrosis factor-α (P < 0.01). Conditioned medium ( CM) from normal villous explants induced endothelial cell migration and in vitro tube formation, which were both attenuated by pre-incubation with exogenous sVEGFR-1 (P < 0.001). In contrast, endothelial cells treated with preeclamptic CM showed substantially reduced angiogenesis compared with normal CM (P < 0.001), which was not further decreased by the addition of exogenous sVEGFR-1, indicating a saturation of the soluble receptor. Removal of sVEGFR-1 by immunoprecipitation from preeclamptic CM significantly restored migration (P < 0.001) and tube formation (P < 0.001) to levels comparable to that induced by normal CM, demonstrating that elevated levels of sVEGFR-1 in preeclampsia are responsible for inhibiting angiogenesis. Our finding demonstrates the dysregulation of the VEGF/PlGF axis in preeclampsia and offers an entirely new therapeutic approach to its treatment.