The regulation of trophoblast migration across endothelial cells by low shear stress: consequences for vascular remodelling in pregnancy

Abstract

In early human pregnancy placental trophoblasts migrate along uterine spiral arteries (SAs) and remodel these vessels into wide-bore conduits in a process essential for successful pregnancy. Until 10-12 weeks gestation trophoblasts plug spiral arteries, resulting in slow, high-resistance blood flow. This work examined the consequences of these low shear stress conditions on trophoblast migration, adhesion molecule expression, and attraction to chemotactic factors. Trophoblasts were cultured on fibronectin or human endothelial cells for 6-12 h under 0.5-6 dyne/cm(2) shear stress using the BioFlux200 system, and imaged by time-lapse microscopy. Computer-based imaging algorithms were developed to automatically quantify migration. Chemotaxis assays were run using parallel flow. Trophoblasts cultured on fibronectin or endothelial cells did not undergo directional migration in 0.5 and 2 dyne/cm(2) cultures; however, in 4 and 6 dyne/cm(2) trophoblasts migrated with the direction of flow (n= 4, P< 0.001). Shear stresses did not affect the speed of trophoblast migration, or adhesion molecule expression (E-selectin, α(4), β(1), and α(v)β(3) integrin). Trophoblasts cultured on endothelial cells migrated into media containing interleukin-8, macrophage chemoattractant protein-1, or Regulated-upon-Activation-Normal-T-cell-Expressed-and-Secreted (RANTES) (n= 5, P< 0.05). Shear stress increases trophoblast migration in the direction of flow, challenging the idea that trophoblasts migrate down spiral arteries retrograde to flow. This suggests that low shear stresses generated by trophoblast plugging of spiral arteries in the first trimester may favour arterial remodelling by preventing the migration with flow seen at higher shear stresses, allowing trophoblasts to migrate down the arteries in response to alternate stimuli such as uterine or endothelial cell-derived chemotactic factors.