ERRγ对胎盘血管生成因子的调节及其在子痫前期发病中的作用机制研究

The pathogenesis of preeclampsia remains unclear. The imbalance between placental anti-angiogenic factors and pro-angiogenic factors can explain the dysfunction of endothelial cells leading to preeclampsia on the second stage of “two-stage model of disease”, but can’t explain the failed remodeling of the maternal vessels on the first stage. And the regulation of these anti-angiogenic factors and pro-angiogenic factors is unclear. Estrogen-related receptor γ (ERRγ) is an oxygen dependent transcription factor. Our previous studies found that ERRγ affected the differentiation and function of human trophoblasts via control of a number of hypertension-associated genes including the voltage-gated potassium channels. ERRγ was associated with preeclampsia. Further, placentas of ERRγ-deficient mice manifested imbalance between placental anti-angiogenic factors and pro-angiogenic factors, compared to wild type mice. So we hypothesize that the aberrant regulation of ERRγ on placental angiogenic factors may play an important role in the pathogenesis of preeclampsia. In this project, we are going to investigate the effect of ERRγ on the remodeling of the maternal vessels of placenta and the regulation of ERRγ on placental angiogenic factors. We are also planning to analyze the blood pressure, protein urine, placental angiogenesis and expression of placental angiogenic factors from wild type pregnant mice injected with ERRγ agonist DY131 or vehicle, which may determine the critical working period of ERRγ. Meanwhile, we are going to determine the relationship of placental ERRγ expression with early-onset preeclampsia. The conclusions of this project may explain the different pathogenesis of early-onset or late-onset preeclampsia and provide a new way for evaluation and treatment of preeclampsia.

子痫前期发生机制不详，胎盘血管生成因子失衡能解释 “二阶段疾病模型”假说中第二阶段这些因子导致广泛内皮损伤，引起子痫前期症状，但不能解释第一阶段如何引起胎盘血管重铸障碍和缺氧，且这些因子的调控机制尚待研究。雌激素相关受体γ （ERRγ）是氧敏感性转录因子。我们的前期研究发现ERRγ能调控人滋养细胞中电压门控钾通道等基因，影响胎盘滋养细胞的分化和功能；ERRγ调控异常与子痫前期密切相关；ERRγ缺陷小鼠胎盘血管增生，VEGF等胎盘血管生成因子失衡。由此我们推测ERRγ通过调控胎盘血管生成因子影响胎盘血管重铸和血管内皮功能，引起子痫前期的发生。本项目通过滋养细胞体系、注射ERRγ激动剂孕鼠模型和人子痫前期病例，研究ERRγ对胎盘血管重铸的影响，明确其调控血管生成因子的分子机制，分析其作用时间和对早发型或迟发型子痫前期的不同作用机制。研究结果将为评估和治疗子痫前期提供崭新思路和途径。

背景：子痫前期是常见的妊娠期合并症，严重威胁母胎安危，但其发生机制不详。根据前期研究，我们推测ERRγ可能通过调控胎盘血管生成因子参与子痫前期的发生。胎儿生长受限（Fetal Growth Restriction, FGR）与子痫前期的发病机制类似，均属于胎盘源性疾病，我们进一步研究ERRγ调控参与FGR发病的分子作用机制。.内容：研究ERRγ调控血管生成因子及影响胎盘血管重铸的机制。研究ERRγ调控因子CXCR2在子痫前期中的发病机制。比较选择性胎儿生长受限（sIUGR）和正常双胎妊娠中子痫前期的发病率，临床表现以及妊娠结局。探究染色体微阵列分析（Chromosomal Microarray Analysis, CMA）技术在FGR产前诊断中的应用。研究ERRγ和17β-羟基类固醇脱氢酶1型（HSD17B1）在FGR和正常妊娠的胎盘中的表达差异以及在FGR发病中的分子作用机制。.结果：在子痫前期和正常单胎妊娠的胎盘中ERRγ和胎盘血管生成因子没有明显的表达差异，检测滋养细胞株ERRγ及血管生成因子的表达无明显差异。子痫前期中CXCR2的mRNA和蛋白质表达水平均显著下降，滋养细胞株沉默表达CXCR2时侵袭能力受抑制，且p-Akt表达水平的下降。子痫前期在sIUGR中的发病率高于正常双胎妊娠， sIUGR分娩发生新生儿重度窒息的机率明显高于正常双胎妊娠。行有创产前诊断的FGR病例中，CMA较传统的染色体核型分析能额外检出11.4%的异常。在中孕期诊断的非匀称性FGR中，CMA比染色体核型分析的异常检出率更高。在FGR中，胎盘ERRγ和HSD17B1的表达均下降。沉默表达ERRγ时，HSD17B1的表达也下降，且细胞的增殖侵袭能力下降。ERRγ通过在其5'-侧翼启动子区域内靶向ERRγ应答元件来刺激HSD17B1的转录。.结论：1）未能证实ERRγ调控VEGF等血管生成因子的表达。2）CXCR2可能通过p-Akt信号通路调节滋养细胞的侵袭能力从而导致子痫前期的发生。3）sIUGR比正常双胎妊娠出现子痫前期的发生率更高，产生不良妊娠结局更严重。4）在中孕期诊断的非匀称性FGR中，染色体微阵列技术比传统的染色体核型分析的异常检出率更高。5）异常ERRγ表达可能通过调节HSD17B1的转录活性而参与FGR的发病机制。