Invasive Trophoblasts Stimulate Vascular Smooth Muscle Cell Apoptosis by a Fas Ligand-Dependent Mechanism

Abstract

During pregnancy, trophoblasts migrate from the placenta into uterine spiral arteries, transforming them into wide channels that lack vasoconstrictive properties. In pathological pregnancies, this process is incomplete. To define the fundamental events involved in spiral artery remodeling, we have studied the effect of trophoblasts on vascular smooth muscle cells (SMCs). Here we demonstrate for the first time that apoptosis of SMCs can be initiated by invading trophoblasts. When trophoblasts isolated from normal placenta (primary trophoblasts) or conditioned medium was perfused into spiral or umbilical artery segments, apoptosis of SMCs resulted. Culture of human aortic SMCs (HASMCs) with primary trophoblasts, primary trophoblast-conditioned medium, or a trophoblast-derived cell line (SGHPL-4) also significantly increased SMC apoptosis. Fas is expressed by spiral artery SMCs, and a Fas-activating antibody triggered HASMC apoptosis. Furthermore, a Fas ligand (FasL)-blocking antibody significantly inhibited HASMC apoptosis induced by primary trophoblasts, SGHPL-4, or trophoblast-conditioned medium. Depleting primary trophoblast-conditioned medium of FasL also abrogated SMC apoptosis in vessels in situ. These results suggest that apoptosis triggered by the release of soluble FasL from invading trophoblasts contributes to the loss of smooth muscle from the walls of spiral arteries during pregnancy.

Fetal-Derived Trophoblast Use the Apoptotic Cytokine Tumor Necrosis Factor-α–Related Apoptosis-Inducing Ligand to Induce Smooth Muscle Cell Death

“…We have previously demonstrated that primary CTB and trophoblast cell lines can initiate endothelial and SMC apoptosis in spiral arteries via the Fas/Fas ligand pathway, and have proposed that a trophoblastdependent apoptotic mechanism contributes to endothelial and SMC loss during remodeling in pregnancy. 10,11 The current study identifies TRAIL as another important apoptotic ligand produced by trophoblast, that is able to induce SMC apoptosis. Here we propose that activation of the TRAIL pathway also contributes to SMC loss during spiral artery remodeling in human pregnancy.…”

“…10,11 Images were analyzed using ImagePro Plus (Media Cybernetics, Silver Spring, Md). Details are provided in the online data supplement.…”

“…9 We have shown that endothelial cells and smooth muscle cells are lost from spiral arteries by trophoblast-induced apoptosis through a mechanism involving activation of the Fas/Fas ligand (FasL) pathway. 10,11 The aim of this study was to investigate other apoptotic ligands produced by trophoblast that may be involved in causing apoptosis of SMC in the vessel wall.…”

Maternal Vascular Physiology in Preeclampsia

“…Remodeling of the spiral arteries involves derangement of their vascular smooth muscle layer and loss of their endothelial lining. 81,82 This results in conversion of the spiral arteries from tightly coiled vessels to low resistance, wide-bore conduits that are not tonically active. In preeclampsia, spiral artery remodeling is incomplete, with some vessels retaining portions of their smooth muscle and others being totally unmodified.…”

Evidence for Immune Cell Involvement in Decidual Spiral Arteriole Remodeling in Early Human Pregnancy

“…The dogma is that invasive EVTs, which detach from placental villous columns anchored to the decidua, mediate the destruction of the vascular wall, either from within the vessel (endovascular (v)EVTs) or from the surrounding decidual stroma (interstitial (i)EVTs). In vitro studies demonstrate that isolated trophoblast cells are capable of triggering apoptosis of VSMCs, potentially via trophoblast-derived Fas ligand and tumor necrosis factor-␣-related apoptosis-inducing ligand, 5,6 and EVTs produce matrix metalloproteinases (MMPs) capable of cleaving substrates in the vascular wall. 7,8 However, apoptotic vascular cell death has not been demonstrated in remodeling vessels in vivo 9 and there is accumulating evidence for remodeling events that precede the appearance of EVT.…”