Liu Wei, Wang Shu-Jun, Lin Qi-De
1. Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China;
2. Shanghai Institute of Immunology, Shanghai, 200025, China.
Int J Biol Sci. 2014 Feb 21;10(3):278-84. doi: 10.7150/ijbs.6375. eCollection 2014.
To investigate the relationship between oxygen sensitivity of trophoblast and hypoxia in preeclamptic placenta by the study on the expressions of hypoxia-inducible factor prolyl 4-hydroxylase (PHD) and hypoxia-inducible factor (HIF) in placentas from normal pregnant women and patients with pre-eclampsia.
Subjects were chosen from the in-patients or the out-patients from May 2003 to May 2004. They were divided into 5 groups: early pregnancy group (EP), 13 cases; middle pregnancy group (MP), 9 cases; late pregnancy group (LP, or control group), 12 cases; preeclampsia (PE) group, 20 cases; gestational hypertension group (GH), 10 cases. The mRNA expressions of PHD-1 and -2 and -3 in placentas from all the subjects were assessed by in situ hybridization and Real-time PCR. The expressions of HIF-1α and -2α in placentas from different groups were assessed by immunohistochemistry and western blot.
PHD-1,-2 and -3 mRNA were mainly expressed in cytoplasm of trophoblast, especially strongly expressed in extravillous trophoblast. During the progress of pregnancy, the expression of PHD-1 increased significantly (R=0.616, P<0.001). The PHD-1mRNA expression in placentas from PE group decreased significantly compared with that from control group, P<0.05. A significant direct correlation between the PHD-1 mRNA expression in placentas from PE group and their placenta weight was found (R=0.457, P<0.05). The HIF-2α, not the HIF-1α expression, from PE group was significantly higher than that from control group, P<0.01; The HIF-2α expression in trophoblast from PE was inversely correlated to the date of the onset of the disease (R=-0.730, P<0.01).
PHD-1 played an important role in hypoxic response pathway of trophoblast through modulating the level of HIF-2α. The overly activated hypoxic response pathway of trophoblast in preeclamptic placenta, which is manifested as the result of HIF-2α over-expression, is the key point to hypoxic dysfunction of trophoblast.
通过研究正常孕妇和子痫前期患者胎盘组织中缺氧诱导因子脯氨酰4-羟化酶（PHD）及缺氧诱导因子（HIF）的表达，探讨滋养细胞氧敏感性与子痫前期胎盘缺氧的关系。
选取2003年5月至2004年5月住院或门诊患者。分为5组：早孕组（EP），13例；中孕组（MP），9例；晚孕组（LP，即对照组），12例；子痫前期（PE）组，20例；妊娠期高血压组（GH），10例。采用原位杂交和实时荧光定量PCR检测所有研究对象胎盘组织中PHD-1、-2、-3的mRNA表达。采用免疫组化和蛋白质印迹法检测不同组胎盘组织中HIF-1α和-2α的表达。
PHD-1、-2、-3 mRNA主要表达于滋养细胞胞质，在绒毛外滋养细胞中表达较强。在妊娠过程中，PHD-1表达显著增加（R=0.616，P<0.001）。PE组胎盘组织中PHD-1 mRNA表达较对照组显著降低，P<0.05。PE组胎盘组织中PHD-1 mRNA表达与胎盘重量呈显著正相关（R=0.457，P<0.05）。PE组HIF-2α而非HIF-1α表达显著高于对照组，P<0.01；PE组滋养细胞中HIF-2α表达与发病孕周呈负相关（R=-0.730，P<0.01）。
PHD-1通过调节HIF-2α水平在滋养细胞缺氧反应途径中起重要作用。子痫前期胎盘滋养细胞缺氧反应途径过度激活，表现为HIF-2α过表达，是滋养细胞缺氧功能障碍的关键所在。
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