Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
FASEB J. 2019 Apr;33(4):5058-5066. doi: 10.1096/fj.201802151RR. Epub 2019 Jan 2.
Systemic endothelial dysfunction is a key characteristic of preeclampsia (PE), which is a serious disorder of human pregnancy. We have previously reported that high-temperature requirement factor (Htr)A4 is a placenta-specific protease that is secreted into the maternal circulation and significantly up-regulated in PE, especially early-onset PE. We have also demonstrated that high levels of HtrA4 detected in the early onset PE circulation induce endothelial dysfunction in HUVECs. In the current study, we investigated whether HtrA4 could cleave the main receptor of VEGFA, the kinase domain receptor (KDR), thereby inhibiting VEGFA signaling. We first demonstrated that HtrA4 cleaved recombinant KDR in vitro. We then confirmed that HtrA4 reduced the level of KDR in HUVECs and inhibited the VEGFA-induced phosphorylation of Akt kinase, which is essential for downstream signaling. Further functional studies demonstrated that HtrA4 prevented the VEGFA-induced tube formation in HUVECs and dose-dependently inhibited the VEGFA-induced angiogenesis in explants of mouse aortic rings. These data strongly suggest that high levels of HtrA4 in the maternal circulation could cleave the main receptor of VEGFA in endothelial cells to induce a wide-spread impairment of angiogenesis. Our studies therefore suggest that HtrA4 is a potential causal factor of early onset PE.-Wang, Y., La, M., Pham, T., Lovrecz, G. O., Nie, G. High levels of HtrA4 detected in preeclamptic circulation may disrupt endothelial cell function by cleaving the main VEGFA receptor KDR.
系统性内皮功能障碍是先兆子痫（PE）的一个关键特征，PE 是一种严重的妊娠疾病。我们之前报道过高热需求因子（Htr）A4 是一种胎盘特异性蛋白酶，可分泌到母体循环中，并在 PE 中显著上调，尤其是早发型 PE。我们还证明，在早发型 PE 循环中检测到的高水平 HtrA4 可诱导 HUVEC 中的内皮功能障碍。在本研究中，我们研究了 HtrA4 是否可以裂解 VEGFA 的主要受体激酶结构域受体（KDR），从而抑制 VEGFA 信号转导。我们首先证明 HtrA4 在体外裂解重组 KDR。然后我们证实 HtrA4 降低了 HUVEC 中的 KDR 水平，并抑制了 VEGFA 诱导的 Akt 激酶磷酸化，这对于下游信号转导至关重要。进一步的功能研究表明，HtrA4 可防止 VEGFA 诱导的 HUVEC 管形成，并呈剂量依赖性抑制小鼠主动脉环外植体中 VEGFA 诱导的血管生成。这些数据强烈表明母体循环中高水平的 HtrA4 可裂解内皮细胞中 VEGFA 的主要受体，从而引起广泛的血管生成受损。因此，我们的研究表明 HtrA4 可能是早发型 PE 的一个潜在因果因素。-Wang, Y., La, M., Pham, T., Lovrecz, G. O., Nie, G. 在子痫前期循环中检测到的高水平 HtrA4 可能通过裂解主要的 VEGFA 受体 KDR 来破坏内皮细胞功能。
