Division of Biomedical Sciences, St George's University of London, Cranmer Tce, London SW17 0RE, UK.
Cardiovasc Res. 2011 Apr 1;90(1):130-9. doi: 10.1093/cvr/cvq396. Epub 2010 Dec 14.
In the first trimester of pregnancy, placental trophoblasts migrate along uterine spiral arteries (SA) and replace endothelial cells (EC) lining these vessels by mechanisms involving EC apoptosis. Inadequate SA remodelling has been associated with pre-eclampsia and intra-uterine growth restriction. Until 10-12 weeks of gestation, trophoblasts plug SA, preventing maternal blood flow into the intervillous space and resulting in high resistance, low shear flow in these vessels. We aimed to determine the effect of shear stress on trophoblast-induced EC apoptosis.
Trophoblasts and human umbilical vein endothelial cells (HUVECs) were cultured for 13-31 h under shear stresses from 0.02 to 7 dyne/cm². Apoptosis was quantified by time-lapse microscopy. Treatment with tumour necrosis factor α/actinomycin D increased apoptotic death in all cell types (P < 0.01). However, trophoblasts cultured in 3 dyne/cm² underwent less apoptosis than those in 0.5 dyne/cm² cultures (P < 0.05). Trophoblasts cultured on HUVEC monolayers at 0.5 or 3 dyne/cm² significantly induced apoptosis in directly adjacent HUVECs, in comparison to HUVECs >2 cells away or HUVEC only controls (P < 0.05), and this was mediated by Fas/Fas-ligand mechanisms. The amount of induced apoptosis decreased from 0.5 to 3 dyne/cm² cultures (P < 0.05), and trophoblasts failed to significantly induce HUVEC apoptosis in 5 or 7 dyne/cm² cultures.
The survival advantage of trophoblasts over EC at low shear stress, and the inhibition of trophoblast-induced EC apoptosis with increasing shear stress, suggests that low shear stresses in plugged first-trimester SA may aid trophoblast-induced EC apoptosis involved in SA remodelling.
在妊娠早期，胎盘滋养层细胞沿着子宫螺旋动脉（SA）迁移，并通过涉及内皮细胞（EC）凋亡的机制取代这些血管的内皮细胞。SA 重塑不足与子痫前期和宫内生长受限有关。在妊娠 10-12 周之前，滋养层细胞堵塞 SA，阻止母体血液流入绒毛间隙，导致这些血管的阻力增加、剪切流降低。我们旨在确定切应力对滋养层诱导的 EC 凋亡的影响。
在 0.02 至 7 达因/平方厘米的切应力下，将滋养层细胞和人脐静脉内皮细胞（HUVEC）培养 13-31 小时。通过延时显微镜定量细胞凋亡。肿瘤坏死因子 α/放线菌素 D 处理增加了所有细胞类型的凋亡死亡（P < 0.01）。然而，与 0.5 达因/平方厘米培养的细胞相比，在 3 达因/平方厘米培养的滋养层细胞发生的凋亡较少（P < 0.05）。在 0.5 或 3 达因/平方厘米的 HUVEC 单层上培养的滋养层细胞与距离>2 个细胞的 HUVEC 或仅 HUVEC 对照相比，显著诱导直接相邻的 HUVEC 凋亡（P < 0.05），这是通过 Fas/Fas 配体机制介导的。与 0.5 达因/平方厘米培养相比，诱导的凋亡量从 0.5 减少到 3 达因/平方厘米培养（P < 0.05），并且滋养层细胞在 5 或 7 达因/平方厘米培养中不能显著诱导 HUVEC 凋亡。
低切应力下滋养层细胞相对于 EC 的生存优势，以及切应力增加抑制滋养层诱导的 EC 凋亡，表明早期妊娠被堵塞的 SA 中的低切应力可能有助于滋养层诱导的参与 SA 重塑的 EC 凋亡。
