Oxidative stress induces smooth muscle dedifferentiation in placental stem villus arteries through reduced hydrogen sulphide production by cystathionine-γ-lyase

Abstract

Introduction: Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality, and is often associated with abnormal Doppler umbilical artery waveforms indicative of increased vascular resistance. The increased resistance is thought to involve stem villus arteries (SVAs), but how it develops remains unknown. Oxidative stress following deficient maternal spiral artery conversion is believed to be the primary insult in unexplained cases of IUGR and pre-eclampsia. Cystathionine-g-lyase (CSE) has been reported to be downregulated in SVAs during IUGR and pre-eclampsia1. Methods: SVA explants from uncomplicated human pregnancies delivered by elective Caesarean section were subjected to oxidative stress in vitro by cycles of hypoxia-reoxygenation (HR), or to normoxia in the presence or absence of CSE inhibitor propargylglycine (10 mM) for 1 or 3 days. Results: HR induced oxidative stress, and vascular smooth muscle (SM) dedifferentiation, with reduced expression of the contractile proteins and differentiation markers SM Myosin Heavy Chain and SM a-actin. SM dedifferentiation was accompanied by acquisition of a synthetic phenotype characterised by increased SM proliferation, and marked ECM remodelling, as evidenced by changes in collagen deposition. HR also reduced CSE expression in SVAs and produced a decline in H2S production of similar magnitude. CSE inhibition under normoxic conditions increased the level of oxidative stress in SVAs and produced changes in SM marker expression similar to those induced by HR. Under oxidative stress, changes in Hsp90 and catalase levels were paradoxically correlated with changes in CSE expression. Conclusions: Our results show that oxidative stress can trigger, via CSE downregulation and reduced H2S signalling, a positive feedback loop of signalling that drives SM dedifferentiation into a synthetic phenotype. This could result in vascular remodelling, leading to compromised SVA distensibility, and hence increased SVA and placental resistance in pathological pregnancies. 1. Cindrova-Davies et al. 2013 Am J Pathol 182,1448-1458.