Decreased expression of fibroblast growth factor 13 in early-onset preeclampsia is associated with the increased trophoblast permeability
Introduction
Preeclampsia (PE) is a life-threatening disease with high morbidity and mortality among the pregnant population, characterized by hypertension, severe proteinuria and pitting edema after 20 weeks of gestation. PE can be classified as early-onset or late-onset according to the gestational time in which it develops. Early-onset PE develops before 34 weeks of gestation. Unlike the normal villous morphology in late-onset PE, early-onset PE is usually concurrent with placental pathology [1,2]. As the maternal-fetal interface, the placenta mediates exchange and immune responses between the mother and fetus. Placental barrier dysfunction has been implicated in PE patients with high risks of abnormal infiltration of leukocytes, fetomaternal hemorrhage (FMH) and placental penetration of apoptotic signaling [[3], [4], [5], [6], [7]]. The physical barrier between the fetal and maternal blood circulation is composed of trophoblasts, which regulate placental permeability and orchestrate the selective secretion and absorption.
Fibroblast growth factor 13 (FGF13), also known as fibroblast growth factor homologous factor 2, belongs to the FGF homologous factor (FHF) subfamily [8]. Unlike other secretory FGF members, FGF13 lacks the N-terminal secretion signal sequence, therefore it acts in an FGFR-independent manner [9]. Previously published studies have reported that FGF13 is principally expressed in the nervous system and functions as an indispensable regulator of neuronal development. For example, FGF13 has been shown to be implicated in the regulation of neurons polarization and migration [10], activation of neural differentiation [11], and the modulation of Na+ currents in neural conduction [12,13]. It also has broad functions in the heart [14,15] and smooth muscle [16]. In addition to the enrichment of FGF13 in the brain, FGF13 is also highly expressed in the female reproductive system, especially in the placenta. Antibody staining has revealed that the protein levels of FGF13 are higher in placental trophoblasts than in follicle cells of the ovary and endometrial stroma cells of the endometrium (results summarized from the Human Protein Atlas Database, http://www.proteinatlas.org/ENSG00000129682-FGF13/tissue). However, the function of FGF13 in human reproduction remains unexplored.
The aims of the current study were to elucidate the potential role of FGF13 in the pathogenesis of early-onset PE and to uncover the related molecular mechanisms. This study discovered that in the human placenta, FGF13 was expressed in villous trophoblasts and was downregulated in the PE placental tissues. Therefore, we hypothesized that the expression of FGF13 regulated early-onset PE pathogenesis. We demonstrated that FGF13 was an important regulator of trophoblast permeability in placental transport and that FGF13 mediated cell junction integrity through the regulation of E-cadherin. These findings unveiled FGF13 as a novel mediator in maintaining placental function, indicating a critical role of the enriched expression of FGF13 in the reproductive system. The significantly downregulated FGF13 levels in PE human villi discovered here suggested its potential translational and clinical implications.
Section snippets
Human placental tissues
Human placental tissues were obtained and used for this study with written patient-informed consent and approval by the Ethics Committee of Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University. The experimental groups included early-onset PE group and control group. PE placental tissues were obtained from 19 patients (age, 22–34 years) with early-onset PE with a terminated pregnancy in the third trimester. The control group included 36 normal pregnancies
Clinical characteristics
The clinical characteristics of all pregnant women were presented in Table 1. There were no significant differences in the maternal ages between two control and the early-onset PE group. The women with early-onset PE suffered from proteinuria and displayed a higher pregestation body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared to the control group. The neonatal birthweight was significantly lower in the early-onset PE group than in the normal
Discussion
PE is one of the most common complications of pregnancy, and its etiology is primarily associated with pathological placentation [[22], [23], [24]]. So far, the clinical treatment for PE has been unsatisfactory [1]. Placental barrier interruption maybe one of the most important stimuli for disease progression [[3], [4], [5], [6], [7]]. Unfortunately, studies on the molecular mechanisms of placental barrier interruption have not fully elucidated this process. Therefore, continuing to search for
Conflicts of interest
None.
Acknowledgements
This work was supported by the National Science Foundation of China 81601317, the Chinese Postdoctoral Fellowship 2015M580726, the National Science Foundation of Guangdong 2017A030313584 (X. Yue); the Special Fund for Cooperative Innovation and Platform Environment Construction 2015B050501006, the Natural Science Foundation of Guangdong Province 2015A030310025, the National Science Foundation of China 81401208, 81671466, the National Innovation and Entrepreneurship Training Program 201612121007
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These authors contributed equally to this work.