Published online before print February 22, 2007, doi: 10.1161/01.RES.0000261352.81736.37
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© 2007 American Heart Association, Inc.
Molecular Medicine |
Fetal-Derived Trophoblast Use the Apoptotic Cytokine Tumor Necrosis Factor-
–Related Apoptosis-Inducing Ligand to Induce Smooth Muscle Cell Death
From the Centre for Developmental and Endocrine Signalling, Division of Basic Medical Sciences (R.J.K., A.F., G.StJ.W., J.E.C.), St. George’s, University of London, Cranmer Terrace, London, UK; and Division of Human Development (L.K.H., P.N.B., J.D.A.), University of Manchester, St. Mary’s Hospital, Hathersage Road, Manchester, UK.
Correspondence to Dr Judith E Cartwright, St George’s Hospital Medical School Department of Biochemistry and Immunology Cranmer Terrace London SW17 0RE United Kingdom. E-mail jcartwri{at}sgul.ac.uk
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.
Key Words: apoptosis • cell death • pregnancy • vascular remodeling • vascular smooth muscle
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Circ. Res. 2007 100: 754-756.
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