Abstract
Pre‐eclampsia (PE) is a life‐threatening multisystem disorder leading to maternal and neonatal mortality and morbidity. Emerging evidence showed that activation of the complement system is implicated in the pathological processes of PE. However, little is known about the detailed cellular and molecular mechanism of complement activation in the development of PE. In this study, we reported that complement 5a (C5a) plays a pivotal role in aberrant placentation, which is essential for the onset of PE. We detected an elevated C5a deposition in macrophages and C5a receptor (C5aR) expression in trophoblasts of pre‐eclamptic placentas. Further study showed that C5a stimulated trophoblasts towards an anti‐angiogenic phenotype by mediating the imbalance of angiogenic factors such as soluble fms‐like tyrosine kinase 1 (sFlt1) and placental growth factor (PIGF). Additionally, C5a inhibited the migration and tube formation of trophoblasts, while, C5aR knockdown with siRNA rescued migration and tube formation abilities. We also found that maternal C5a serum level was increased in women with PE and was positively correlated with maternal blood pressure and arterial stiffness. These results demonstrated that the placental C5a/C5aR pathway contributed to the development of PE by regulating placental trophoblasts dysfunctions, suggesting that C5a may be a novel therapeutic possibility for the disease.
Highlights
PE, characterized by new-onset hypertension and proteinuria, is a severe obstetric complication leading to maternal and foetal morbidity and mortality [1, 2]
Our findings indicated that activation of complement 5a (C5a) in placenta could regulate the function of trophoblast cells
Placental C5a interact with its receptor C5a receptor (C5aR), interrupts trophoblasts function via inhibiting the migration, tube formation and angiogenesis of trophoblasts
Summary
PE, characterized by new-onset hypertension and proteinuria, is a severe obstetric complication leading to maternal and foetal morbidity and mortality [1, 2]. Previous study showed that complement C1q prevents the development of PE through regulating placental oxidative stress and angiogenic molecule expression. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine Wang et al reported that angiotensin II type 1 receptor agonistic autoantibody contributes to C3 and C3aR signalling is a key mechanism underlying the pathogenesis of PE [14]. As a key downstream component of the complement cascade, C5a exerts a pro-inflammatory effect by binding to its respective receptor, C5aR [15]. We investigated the effect of the C5a/C5aR pathway on trophoblasts and the association between C5a and maternal arterial stiffness
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