Differential expression and the anti-apoptotic effect of human placental neurotrophins and their receptors

Abstract

Neurotrophin (NT) is important in the survival, maintenance and differentiation of neuronal tissue, and functions in follicle maturation, tumor growth, angiogenesis and immunomodulation; however, the expression of NT and its receptors (NTR) in human placenta and their influence on fetal growth are unclear. Here we investigated the correlation of NT and NTR in human placenta with uterine environment and fetal growth. TrkB, a NTR, mRNA was expressed on decidual and villous tissue and increased with gestational age, localizing in the trophoblast layer and endothelium by immunohistochemistry. Villous TrkB mRNA was significantly increased in preeclampsia (PE) than in controls and was higher in the normotensive small for gestational age (SGA) placenta, although it was not significant. It was also significantly increased in the small twin of discordant twin pregnancies. Brain-derived neurotrophic factor (BDNF), the main ligand of TrkB, was expressed in membranous chorion and villous tissue and was significantly higher in maternal plasma in normotensive SGA and PE than in controls. TrkB mRNA expression was up-regulated on cultured villous tissue explants and on JEG-3, a choriocarcinoma cell line, by H₂O₂ treatment. BDNF decreased apoptotic cells in H₂O₂-treated JEG-3, indicating that BDNF/TrkB signaling had anti-apoptotic effects against oxidative stress in JEG-3, suggesting a protective role of BDNF/TrkB in human villous tissue under unfavorable conditions in utero.

Introduction

Preeclampsia (PE) is a pregnancy-induced disease characterized by elevated blood pressure and proteinuria after 20 weeks of gestation. The disease is estimated to occur in 3–5% of pregnancies. Especially in early onset or in severe type, PE is one of the major causes of maternal mortality because of its severe symptoms (e.g. HELLP syndrome, eclampsia, renal failure) in addition to causing fetal and neonatal mortality by preterm birth or intra-uterine growth restriction (IUGR) [1]. A number of studies have suggested possible mechanisms for the development of PE, including shallow trophoblast invasion and impaired spiral artery remodeling [2] with subsequent placental hypoperfusion and endothelial dysfunction. In addition, a variety of factors are thought to contribute to the pathogenesis of PE: inflammation [3], immune maladaptation [4] and metabolic disorders [5]. Increased placental apoptosis is reported to be observed in PE and IUGR by a variety of stimuli and damage, including hypoxia and oxidative stress [6], [7], [8]. Despite the progress of clinical and basic researches, the cause of PE has not been completely elucidated and there is no specific therapy except for placental delivery. It is known that some growth factors, including epidermal growth factor (EGF) and insulin-like growth factor (IGF), can rescue trophoblast apoptosis mediated by cytokine or oxidative stress in vitro [9], [10]. These are examples of the potent protective mechanisms against various stresses in the feto-maternal environment.

Neurotrophin (NT) is known to be an important factor in the survival, maintenance and differentiation of neuronal tissue [11], [12], [13]. The NT family is composed of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Although they share greater than 80% identity in their amino acid structure, each NT interacts with a specific high-affinity tropomyosin-related kinase (Trk) receptor: NGF activates TrkA, BDNF and NT-4 activate TrkB, and NT-3 activates TrkC [14]. Recently, NT has also been reported to play an important role in follicle maturation [15], tumor growth [16], angiogenesis [17], [18], [19], immunomodulation [20], [21], inflammation [22], [23], energy metabolism [24], and so on. Moreover, signaling mediated by BDNF through its receptor TrkB has been reported to play an important role in embryo implantation, subsequent placental development and fetal growth by increasing trophoblast cell growth and survival in mice [25]; therefore, we hypothesized that the NT/NTR system can also play an important role in the human placenta, as reported in neural or some non-neural tissue.

There are a few reports about their expressions on human placenta and fetal membranes. Toti et al. reported that NGF was expressed in human placenta [26] and Casciaro et al. reported that NT-3 was expressed in human placenta [27]; however, the overall expression profile of NT and its receptors (NTR) on human placenta and their influences on fetal growth and pathological pregnancy, such as PE and IUGR, are not well elucidated. Here, we tested the hypothesis that NT and NTR might have an important role in fetal growth and an unfavorable environment, especially in the feto-maternal interface. The aim of this study was to investigate the expression profile of NT/NTR in human placenta and maternal plasma, especially in association with PE and/or fetal growth, and to assess their roles in the pathological environment.