Preeclampsia (PE) is a pregnancy-specific disorder. An important pathological feature of PE is imbalance between pro- and anti-angiogenic factors in the maternal circulation, leading to systemic maternal endothelial dysfunction. Inhibition of TGF-β signalling is closely linked to endothelial dysfunction and PE development.
HtrA serine proteins (especially HtrA3) are important for placental development and HtrA3 dys-regulation during placentation is associated with increased risks of PE. HtrA proteins are known to inhibit TGF-β signalling. Recent transcriptomic studies suggest that HtrA4, another family member closed related to HtrA3, is up-regulated in PE placentas. However, no functional studies have investigated the role of HtrA4 in the pathogenesis of PE.
In this study we discovered by mining microarray depositories and by RT-PCR of human tissues and cell lines that HtrA4 was highly placental specific. We next investigated the levels of circulating HtrA4 in pregnant women at the time of PE presentation. Serum HtrA4 was detected at higher levels in sera from women with PE and the levels were significantly elevated in patients with early onset (28-34 wks) PE compared to gestation-matched controls. Using in vitro endothelial tube assay, we discovered that recombinant HtrA4 disturbed capillary tube formation of HUVEC on matrigel in a dose dependent manner, strongly suggesting an anti-angiogenic function of HtrA4. We further established that HtrA4 inhibited TGF-β signalling, because TGF-β1-induced luciferase activities were progressively lost in HEK293 cells when increasing amounts of HtrA4 were co-transfected.
This study thus strongly suggests that HtrA4 is a novel factor elevated in early onset of PE and that high HtrA4 levels in maternal circulation may cause endothelial dysfunction via inhibition of the TGF-β signalling.