Increasing evidence suggests that complement activation plays a vital role in the pathogenesis of preeclampsia (PE). However, little is known about the detailed cellular and molecular mechanism of complement activation in the development of PE. Here we investigate that whether macrophage-derived complement C5a contributes to the pathophysiology of PE through its effect on trophoblasts.Design and method:
A total of 55 women (32 healthy pregnant women and 23 women with PE) were recruited. Clinical characteristics and vascular function (PWV, ABI) were detected. Placentas (N = 12) were obtained immediately after delivery. C5a, C5a receptor (C5aR), CD31 (endothelium), CD11b (macrophages) and cytokeratin 7 (trophoblast) were detected by immunofluorescent staining. The serum level of C5a was measured by ELISA.Results:
We detected an elevated C5a deposition in the placenta of patients with preeclampsia, which was colocalized with macrophages. C5aR was found highly expressed in syncytiotrophoblasts. In cultured trophoblast cell lines, C5aR agonist peptide inhibited the migration and angiogenesis of trophoblasts. C5aR agonist peptide stimulation also resulted in increased anti-angiogenic factors gene level as IL6, MCP1 and sFlt1, but decreased pro-angiogenic factors gene level as IL-10 and HIF1a. In maternal circulation, the concentration of C5a was higher in women with PE compared to healthy pregnant women (99.75 ± 29.27ng/ml vs 76.35 ± 16.97ng/ml Mean ± SD P < 0.01). Women with PE displayed poor arterial function, which was positively correlated with C5a level. We also observed an increased percentage of proinflammatory M1 monocytes in peripheral blood of women with PE, which was associated with an increased level of C5a.Conclusions:
Our data suggest that macrophages-derived C5a contributed to the poor perfusion of placenta by mediating migration and angiogenesis of trophoblast cells via C5aR. In addition, C5a in the maternal circulation was correlated with the degree of arterial stiffness. Overall, C5a may have a novel role as a mediator of pathogenesis of PE, which could potentially result in gestational vascular dysfunction.