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

Abstract

Abstract-Remodeling of the uterine spiral arteries during pregnancy transforms them from high to low resistance vessels that lack vasoconstrictive properties. This process is essential to meet the demand for increased blood flow imposed by the growing fetus. Loss of endothelial and smooth muscle cells (SMC) is evident in remodeled arteries but the mechanisms underlying this transformation remain unknown. This study investigated the hypothesis that fetal trophoblast invading from the placenta instigate remodeling by triggering cell death in vascular SMC. Specifically, a role for trophoblast-derived death inducing cytokine tumor necrosis factor-␣-related apoptosis-inducing ligand (TRAIL) was investigated. Expression of the activating TRAIL receptors R1 and R2 was detected by flow cytometry on human aortic SMC and by immunohistochemistry on spiral artery SMC. Recombinant human TRAIL induced human aortic SMC apoptosis, which was inhibited by antibodies against TRAIL-R1 or -R2. Perfusion of denuded spiral artery segments with recombinant human TRAIL also induced SMC apoptosis. Trophoblasts isolated from first trimester placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic SMC; apoptosis was significantly inhibited by a recombinant human TRAIL-R1:Fc construct. Trophoblast within the first trimester placental bed also expressed TRAIL. These data show that: 1) TRAIL causes SMC death; 2) trophoblast produce the apoptotic cytokine TRAIL; and 3) trophoblast induce SMC apoptosis via a TRAIL-dependent mechanism. We conclude that TRAIL produced by trophoblast causes apoptosis of SMC and thus may contribute to SMC loss during spiral artery remodeling in pregnancy. (Circ Res. 2007;100:834-841.)

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

“…Studies in vitro have shown that vEVTs can induce VSMC apoptosis. 5,6 Currently there are no reports of apoptosis in remodeling vessels in vivo; and a recent report described the failure to identify apoptotic VSMCs. 9 Using serial immunohistochemistry and dual immunofluorescence, we detected TUNEL-positive nuclei in VSMCs and endothelial cells of arteries exhibiting signs of VSMC disruption and loss (predominantly in stage II).…”

“…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.…”

Signaling Pathways for B Cell-Activating Factor (BAFF) and a Proliferation-Inducing Ligand (APRIL) in Human Placenta

“…Certain cytokines and growth factors originally identified in the immune system are now known to influence reproduction and embryogenesis. This is the case with tumor necrosis factor ␣, 32 two other TNFSF ligands, ie, LIGHT 33,34 and TRAIL (tumor necrosis factor apoptosis-inducing ligand), 35 and two unrelated cytokines, colony-stimulating factor-1 36 and transforming growth factor-␤. 37 The same is very likely also to be true of the B-cell regulators, BAFF and APRIL.…”

Effects of Placental Factors Upon Development of Tubular Structures by Endothelial Cells in Presence of Trophoblastic Cells

“…Trophoblast cells express FasL and secrete its soluble form -sFasL, which interaction with Fas molecule expressed on EC [15,25] leads to the apoptosis of EC. The development of TRAIL-dependent EC apoptosis was also shown [29]. These mechanisms may also be involved in reducing the number of tube-like structures formed by EC cell in the presence of conditioned media of women's placentas.…”