Shear stress and spiral artery remodelling: the effects of low shear stress on trophoblast-induced endothelial cell apoptosis

Aims 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. Methods and results Trophoblasts and human umbilical vein endothelial cells (HUVECs) were cultured for 13-31 h under shear stresses from 0.02 to 7 dyne/cm(2). Apoptosis was quantified by time-lapse microscopy. Treatment with tumour necrosis factor a/actinomycin D increased apoptotic death in all cell types (P < 0.01). However, trophoblasts cultured in 3 dyne/cm(2) underwent less apoptosis than those in 0.5 dyne/cm(2) cultures (P < 0.05). Trophoblasts cultured on HUVEC monolayers at 0.5 or 3 dyne/cm(2) 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/cm(2) cultures (P < 0.05), and trophoblasts failed to significantly induce HUVEC apoptosis in 5 or 7 dyne/cm(2) cultures. Conclusion 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.