缺氧诱导因子1α及其靶基因在子痫前期患者胎盘组织中的表达

Expression of hypoxia-inducible factor-1α,vascular endothelial growth factor and sFlt-1 in preeclampsia placenta

目的探讨缺氧诱导因子1α(HIF-1α)及其靶基因血管内皮细胞生长因子(VEGF)、可溶性血管内皮细胞生长因子受体1(sFlt-1)基因在子痫前期患者胎盘组织中的表达。方法采用免疫组化链霉菌抗生物素蛋白-过氧化物酶连接(SP)法对20例重度子痫前期患者(子痫前期组)和15例正常妊娠妇女(对照组)的胎盘组织中的HIF-1α、VEGF、sFlt-1蛋白表达进行检测；同时应用RT- PCR技术对两组孕妇胎盘组织中HIF-1α、VEGF、sFlt-1 mRNA水平进行检测,并进行相关性分析。结果(1)子痫前期组HIF-1α蛋白表达(+++)者9例(45%,9/20),sFlt-1蛋白表达(+++)者11例(55%,11/20),对照组分别为2例(13%,2/15)和3例(20%,3/15),两组分别比较,差异均有统计学意义(P＜0．05)；子痫前期组VEGF蛋白表达(+++)者3例(15%,3/20),明显低于对照组的7例(47%,7/15),两组比较,差异有统计学意义(P＜0．01)。(2)子痫前期组HIF-1αmRNA、sFlt-1 mRNA水平分别为0．604±0．013、0．898±0．041,对照组分别为0．208±0．007、0．559±0．244,两组分别比较,差异均有统计学意义(P＜0．05)；子痫前期组VEGF mRNA表达水平虽高于对照组,但差异无统计学意义(P＞0．05)。子痫前期组VEGF mRNA/sFlt-1 mRNA比值(0．439±0．009)低于对照组(0．824±0．011),两组比较,差异有统计学意义(P＜0．05)。(3)子痫前期组HIF-1αmRNA的表达与sFlt-1 mRNA表达呈正相关(r=0．577,P＜0．05),与VEGF mRNA/sFlt-1 mRNA比值呈负相关(r= -0．376,P＜0．05)。结论HIF-1α在子痫前期患者胎盘组织中表达水平明显升高,主要是通过调节VEGF、sFlt-1基因的转录,而影响滋养细胞的浸润和胎盘血管重铸,参与子痫前期的发病。

Objective To investigate the expression and correlation of hypoxia-inducible factor-1α （ factor-1α） , vascular endothelial growth factor （VEGF） and sFlt-1 in the preeclampsia placenta, and discuss their significance in the pathogenesis of preeclampsia. Methods Placentas were collected from 20 pregnant women with preeclampsia as study group and 15 normal pregnant women as control group. The expressions of HIF-1α,VEGF and sFlt-1 protein were semi-quantitatively analyzed with immunohistochemical assay and mRNA level was determined using reverse transcription polymerase chain reaction （ RT-PCR ） technique. Results （ 1 ） the expression of factor-1α and sFlt-1 protein in preeclampsia group obviously increased. Strong （ ± ± ± ） positive expression was observed in 9 and 11 cases respectively, significantly higher than in control group （2 and 3 cases ） （ P 〈 0. 05 ） , however, VEGF expression obviously reduced in preeclampsia group（P 〈0. 01 ）. （2）the level of HIF-1α and sFh-1 mRNA in preeclamptic placenta was 0. 604 ±0. 013, 0. 898 ±0. 041, significantly higher than 0. 208 ±0. 007 and 0. 559 ±0. 244 in normal placenta （P 〈0. 05）. Although the level of VEGF mRNA increased in preeclampsia placenta, it was not significantly different from that in normal placenta （ P 〉 0. 05 ） . The ratio of VEGF mRNA /sFlt-1 mRNA obviously reduced in preeclampsia group and was significantly lower than in control group （ P 〈 0. 05 ）. （ 3 ） in preeclampsia group, HIF-1α mRNA expression was positively correlated with the expression of sFlt-1 mRNA（r = 0. 577, P 〈 0. 05）, and negatively correlated with the ratio of VEGF mRNA /sFlt-1 mRNA （r = - 0. 376, P 〈 0. 05）. Conclusion Abnormal high HIF-1α expression in preeclampsia placenta indicates that HIF-1α might play an important role in the pathogenesis of preeclampsia, possibly through affecting the cytotrophoblastic invasion and placental vascular reconstruction via the modulation of VEGF and sFlt-1 gene transcription.