Uterine Spiral Artery Remodeling Involves Endothelial Apoptosis Induced by Extravillous Trophoblasts Through Fas/FasL Interactions

Abstract

Objective— Invasion of uterine spiral arteries by extravillous trophoblasts in the first trimester of pregnancy results in loss of endothelial and musculoelastic layers. This remodeling is crucial for an adequate blood supply to the fetus with a failure to remodel implicated in the etiology of the hypertensive disorder preeclampsia. The mechanism by which trophoblasts induce this key process is unknown. This study gives the first insights into the potential mechanisms involved. Methods and Results— Spiral arteries were dissected from nonplacental bed biopsies obtained at Caesarean section, and a novel model was used to mimic in vivo events. Arteries were cultured with trophoblasts in the lumen, and apoptotic changes in the endothelial layer were detected after 20 hours, leading to loss of endothelium by 96 hours. In vitro, coculture experiments showed that trophoblasts stimulated apoptosis of primary decidual endothelial cells and an endothelial cell line. This was blocked by caspase inhibition and NOK2, ... Remodeling of uterine spiral arteries occurs in the first trimester of pregnancy, with failed remodeling a characteristic of preeclampsia. This study gives the first insights into the possible mechanisms involved in this remodeling and suggests that trophoblast induction of endothelial apoptosis through Fas/FasL interactions may be important.