Heazell A E P, Lacey H A, Jones C J P, Huppertz B, Baker P N, Crocker I P
University of Manchester, St Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK.
Placenta. 2008 Feb;29(2):175-86. doi: 10.1016/j.placenta.2007.11.002. Epub 2007 Dec 21.
Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with aberrant cell turnover, including increased apoptosis, in placental villous trophoblast. The increased apoptosis is associated with exaggerated expression of p53, which promotes cell cycle arrest or apoptosis via downstream proteins such as p21 or Bax. These changes in apoptosis and p53 expression are purported to result from exposure to altered oxygen tension. Using a model of villous trophoblast turnover, we examined the effect of 20%, 6% and 1% ambient oxygen (O(2)) on apoptosis, necrosis, proliferation and expression of p53 and related regulators of cell turnover, compared to both fresh tissue. Altered O(2) tension exerted an effect on cell turnover in cultured term villous tissue: cytotrophoblast proliferation was increased by culture in 20% O(2) and reduced in 1% O(2) (median proliferative index: fresh tissue=0.32%, 20% O(2)=0.9%, 6% O(2)=0.28%, 1% O(2)=0.07%). Apoptosis was increased in all culture environments, but was significantly enhanced by culture in 1% O(2) (median apoptotic index: fresh tissue=0.64%, 20% O(2)=2.96%, 6% O(2)=3.81%, 1% O(2)=9.2%). Necrotic cell death was also increased by culture in 1% O(2) compared to 6% and 20% O(2). The expression of p53, p21 and Mdm2 in both cytotrophoblast and stromal cells was increased following culture in 1% O(2). There was no alteration in the expression of Bax or Bcl-2. This study provides evidence that p53 is elevated in trophoblast following exposure to hypoxia. The potential role of the p53-pathway in the control of cell turnover in villous trophoblast and the regulation of p53 by altered O(2) tension merits further investigation.
子痫前期（PE）和胎儿宫内生长受限（IUGR）与胎盘绒毛滋养层细胞异常更新有关，包括细胞凋亡增加。细胞凋亡增加与p53表达过度有关，p53通过p21或Bax等下游蛋白促进细胞周期停滞或凋亡。据推测，细胞凋亡和p53表达的这些变化是由于暴露于改变的氧张力所致。我们使用绒毛滋养层细胞更新模型，与新鲜组织相比，研究了20%、6%和1%的环境氧（O₂）对细胞凋亡、坏死、增殖以及p53和相关细胞更新调节因子表达的影响。氧张力改变对足月绒毛组织培养中的细胞更新产生影响：在20% O₂中培养时，细胞滋养层增殖增加，而在1% O₂中培养时则减少（中位增殖指数：新鲜组织=0.32%，20% O₂=0.9%，6% O₂=0.28%，1% O₂=0.07%）。在所有培养环境中细胞凋亡均增加，但在1% O₂中培养时显著增强（中位凋亡指数：新鲜组织=0.64%，20% O₂=2.96%，6% O₂=3.81%，1% O₂=9.2%）。与6%和20% O₂相比，在1% O₂中培养时坏死性细胞死亡也增加。在1% O₂中培养后，细胞滋养层和基质细胞中p53、p21和Mdm2的表达均增加。Bax或Bcl-2的表达没有改变。本研究提供了证据表明，缺氧后滋养层中p53升高。p53通路在绒毛滋养层细胞更新控制中的潜在作用以及氧张力改变对p53的调节值得进一步研究。
