Hum. Reprod. Advance Access published online on September 27, 2007
Human Reproduction, doi:10.1093/humrep/dem303
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BeWo cells stimulate smooth muscle cell apoptosis and elastin breakdown in a model of spiral artery transformation
1 Maternal and Fetal Health Research Centre, Maternal and Fetal Health Research Group, University of Manchester, St. Mary's Hospital, Manchester M13 0JH, UK 2 Centre for Developmental and Endocrine Signalling, Division of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK
3 Correspondence address. Tel: +44-161-276-6487; Fax: +44-161-276-6134; E-mail: john.aplin{at}manchester.ac.uk
BACKGROUND: During pregnancy, extravillous trophoblast invades the uterine wall and enters the spiral arteries. Remodelling ensues, with loss of vascular smooth muscle cells (SMCs) to create high flow, low resistance vessels. Pregnancies complicated by pre-eclampsia are characterized by incomplete arterial remodelling. Endovascular trophoblast is not easily accessible for studies to establish the pathogenesis of pre-eclampsia, so we have developed a model appropriate to carry out mechanistic studies of vessel wall transformation.
METHODS AND RESULTS: Segments of human spiral artery were perfused with the choriocarcinoma cell line, BeWo; cells invaded the vessel wall and induced apoptosis of vascular SMC. Perfusion of vessels with BeWo-conditioned medium also induced SMC apoptosis, indicating the presence of a soluble apoptotic factor. BeWo express Fas ligand (FasL) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Treatment of BeWo-conditioned medium with antibodies against FasL inhibited vascular SMC apoptosis in vitro. Antibodies that blocked TRAIL receptor function had no effect. Extracellular matrix degradation is also a prerequisite for vascular remodelling; BeWo express matrix metalloproteinase-12 (MMP-12) and BeWo-conditioned medium increased MMP-12 expression in spiral artery SMC.
CONCLUSIONS: BeWo induce arterial remodelling via FasL- and MMP-12-dependent mechanisms. BeWo-derived factors up-regulate protease expression in spiral artery SMC to facilitate matrix breakdown.
Key words: apoptosis/Fas ligand/matrix metalloproteinase/trophoblast invasion/vascular remodelling
Submitted on May 4, 2007; resubmitted on July 2, 2007; accepted on August 28, 2007.
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