P26 Placental stem villus arteries undergo dedifferentiation via reduced hydrogen sulfide production by cystathionine-γ-lyase upon exposure to oxidative stress

Abstract

Introduction Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality, and is often associated with abnormal umbilical artery Doppler 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- γ -lyase (CSE) has been reported to be downregulated in SVAs during IUGR and pre-eclampsia [1] . 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. We additionally analysed the protein sequences obtained from the Human Protein Reference Database to look for potential cysteine changes in the vasculature. 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 α -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 H 2 S 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. Finally, protein sequences obtained from the Human Protein Reference Database revealed cysteine enrichment in vascular tissues compared to other tissues. This was due to the presence of a subset of cysteine-rich extracellular proteins, and suggests H 2 S may act via protein S-sulfhydration in SVAs, including on extracellular targets. Conclusions Our results show that oxidative stress can trigger, via CSE downregulation and reduced H 2 S 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.