Decorin expression is decreased in first trimester placental tissue from pregnancies with small for gestation age infants at birth

Highlights

• Placental decorin (DCN) expression may contribute to the etiology of FGR.

• Small for gestation (SGA) is often used as a surrogate for FGR.

• First trimester placental tissues subsequently developed SGA was investigated.

• Placental DCN expression is significantly reduced in first trimester SGA at birth.

• A temporal relationship is observed for placental DCN expression and SGA.

Abstract

Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. FGR pregnancies are often associated with histological evidence of placental vascular thrombosis. The proteoglycans are important components and regulators of vascular homeostasis. Previous studies from our laboratory highlighted mRNA and protein expression differences in placental proteoglycan decorin (DCN), within a clinically well-characterised cohort of third-trimester idiopathic FGR compared with gestation-matched uncomplicated control pregnancies. We also showed that decorin contributes to abnormal angiogenesis and increased thrombin generation in vitro. These observations suggest that DCN gene expression may contribute to the etiology of FGR. Small for gestational age (SGA) is frequently used as a proxy for FGR and is defined as a birth weight below the 10th percentile of a birth weight curve. We therefore made use of a unique resource of first trimester tissues obtained via chorionic villus sampling during the first trimester to investigate the temporal relationship between altered DCN expression and any subsequent development of SGA. We hypothesized that placental DCN expression is decreased early in gestation in SGA pregnancies. Surplus chorionic villus specimens from 15 women subsequently diagnosed with FGR and 50 from women with uncomplicated pregnancies were collected. DCN mRNA and DCN protein were determined using real-time PCR and immunoblotting, respectively. Both DCN mRNA and protein were significantly decreased in placentae from first-trimester SGA-pregnancies compared with controls (p < 0.05). This is the first study to report a temporal relationship between altered placental DCN expression and subsequent development of SGA.

Introduction

Fetal growth restriction (FGR) is a significant pregnancy disorder that has major consequences for the fetus and neonate as well as an increased risk of long-term morbidity extending into adulthood. Small for gestational age (SGA) is often used as a surrogate for FGR and is defined as a birth weight below the 10th percentile on a birth weight curve [1]. While a number of maternal and fetal factors which contribute to FGR have been identified, the etiologies of the majority of cases remain uncertain [1]. FGR pregnancies are often associated with histological evidence of placental vascular thrombosis, more specifically microvascular thrombosis within the placenta [2], [3], [4].

Recent studies from our laboratory reported that altered placental proteoglycan expression and function may contribute to the coagulation disturbance that leads to maternal-placental vascular thrombosis in third trimester FGR pregnancies. Proteoglycans are macromolecules located within vessel walls that contain a core protein to which sulphated glycosaminoglycan (GAG) chains are covalently linked. There are four types of GAG chains located in the blood vessel wall; chondroitin sulphate, dermatan sulphate, heparan sulphate, and hyaluronan [5]. However, only chondroitin sulphate, dermatan sulphate, and heparan sulphate are covalently linked to a core protein [5]. The placenta contains two major types of proteoglycans; those containing heparan sulphate and those containing chondroitin sulphate or dermatan sulphate [6], [7], [8], [9]. Decorin (DCN) usually has one chondroitin sulphate or dermatan sulphate GAG attached to its core protein.

We previously demonstrated that DCN protein is localised to the stroma surrounding fetal blood vessels of the third trimester placental villi and its expression is decreased in placentae obtained from third trimester FGR-affected pregnancies [10]. Analysis of mice with targeted deletion of the Dcn gene provided conclusive evidence for a role of the Dcn gene in the causal link to preterm birth and reduced birth weight in the offspring [11]. However, determining the cause of human FGR remains a major challenge in human pregnancy research. Uncertainties still exist as to whether the decreased placental DCN expression observed in third trimester human FGR-affected pregnancies is truly causative or rather reflects a response to an altered growth process.

We therefore made use of a unique resource of first trimester tissues obtained via chorionic villus sampling during the first trimester to investigate the temporal relationship between altered decorin expression and any subsequent development of SGA. We hypothesized that placental DCN expression is decreased early in gestation in SGA pregnancies. Early gestation sampling can be accomplished by chorionic villus sampling (CVS), a procedure generally performed between 10 and 14 weeks' gestation. Differentiation of normal from pathological groups is possible, as the eventual maternal and fetal outcomes of ongoing pregnancies are determinable [12], [13]. The aim of this study was to quantify DCN gene expression using real-time PCR in placental tissues collected during CVS performed at first trimester (10–12 weeks' gestation) from on-going pregnancies with known clinical outcomes, i.e. SGA or uncomplicated control pregnancies.