Placental Stem Villus Arterial Remodeling Associated with Reduced Hydrogen Sulfide Synthesis Contributes to Human Fetal Growth Restriction

Liangjian Lu,John Kingdom,Graham J Burton,Tereza Cindrova-Davies

doi:10.1016/j.ajpath.2016.12.002

Abstract

Intrauterine fetal growth restriction (IUGR) is often associated with compromised umbilical arterial flow, indicating increased placental vascular resistance. Oxidative stress is causatively implicated. Hydrogen sulfide maintains differentiated smooth muscle in vascular beds, and its synthetic enzymecystathionine-γ-lyase (CSE) is down-regulated in growth-restricted placentas. We hypothesized that remodeling of resistance arteries in stem villi contributes to IUGR by compromising umbilical blood flow via oxidative stress, reducing hydrogen sulfide signaling. Stem villus arteries in human IUGR placentasdisplaying absent or reversed end-diastolic flow contained reduced myosin heavy chain, smooth muscle actin, and desmin, and increased markers of dedifferentiation, cellular retinol-binding protein 1, and matrix metalloproteinase 2, compared to term and preterm controls. Wall thickness/lumen ratio was increased, lumen diameter decreased, but wall thickness remained unchanged in IUGR placentas. CSE correlated positively with myosin heavy chain, smooth muscle actin, and desmin. Birth weight correlated positively with CSE, myosin heavy chain, smooth muscle actin, and desmin, and negatively with cellular retinol-binding protein 1 and matrix metalloproteinase 2. These findings could be recapitulated invitro by subjecting stem villus artery explants to hypoxia-reoxygenation, or inhibiting CSE. Treatment with a hydrogen sulfide donor, diallyl trisulfide, prevented these changes. IUGR is associated with vascular remodeling of the stem villus arteries. Oxidative stress results in reduction of placental CSE activity, decreased hydrogen sulfide production, and smooth muscle cell dedifferentiation invitro. This vascular remodeling isreversible,and hydrogen sulfide donors are likely to improve pregnancy outcomes.

Highlights

Intrauterine fetal growth restriction (IUGR) is often associated with compromised umbilical arterial flow, indicating increased placental vascular resistance
We attempted to recapitulate the changes seen in the vascular tree of IUGR placentas by subjecting stem villus artery explants dissected from healthy term placentas to oxidative stress induced by HR in vitro for 3 days
The HR challenge had a profound effect on reducing the markers of smooth muscle cells (SMCs) differentiation, myosin heavy chain (MHC) and smooth muscle actin (SMA), and desmin, and increasing the dedifferentiation marker CRBP1, compared to normoxic controls (Figure 5A)

Summary

Introduction

Intrauterine fetal growth restriction (IUGR) is often associated with compromised umbilical arterial flow, indicating increased placental vascular resistance. We hypothesized that remodeling of resistance arteries in stem villi contributes to IUGR by compromising umbilical blood flow via oxidative stress, reducing hydrogen sulfide signaling. Stem villus arteries in human IUGR placentas displaying absent or reversed end-diastolic flow contained reduced myosin heavy chain, smooth muscle actin, and desmin, and increased markers of dedifferentiation, cellular retinol-binding protein 1, and matrix metalloproteinase 2, compared to term and preterm controls. Birth weight correlated positively with CSE, myosin heavy chain, smooth muscle actin, and desmin, and negatively with cellular retinolbinding protein 1 and matrix metalloproteinase 2 These findings could be recapitulated in vitro by subjecting stem villus artery explants to hypoxia-reoxygenation, or inhibiting CSE. Oxidative stress results in reduction of placental CSE activity, decreased hydrogen sulfide production, and smooth muscle cell dedifferentiation in vitro This vascular remodeling is reversible, and hydrogen sulfide donors are likely to improve pregnancy outcomes. Failure of remodeling is associated with IUGR and preeclampsia, when the resultant malperfusion is believed to induce placental oxidative stress.[11,12]

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Results

Conclusion