Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, 3168, Australia.
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, 3800, Australia.
Sci Rep. 2019 Feb 25;9(1):2728. doi: 10.1038/s41598-019-39565-9.
Preeclampsia (PE) is a life-threatening complication of human pregnancy with no effective treatment other than premature delivery. It is hallmarked by systemic endothelial injury/dysfunction which is believed to be caused by abnormal levels/types of placenta-derived factors that are circulating in the maternal blood. Emerging evidence suggests that endothelial repair is also dysregulated in PE, as circulating endothelial progenitor cells (EPCs) critical for endothelial regeneration are reduced in number and functionality. However, the underlying mechanisms are poorly understood. HtrA4 is a placenta-specific protease that is secreted into the circulation and significantly elevated in early-onset PE. Here we investigated the impact of HtrA4 on endothelial proliferation and repair. We demonstrated that high levels of HtrA4 halted endothelial cell proliferation and significantly down-regulated a number of genes that are critical for cell cycle progression, including CDKN3, BIRC5, CDK1 and MKI67. Furthermore, HtrA4 significantly inhibited the proliferation of primary EPCs isolated from term human umbilical cord blood and impeded their differentiation into mature endothelial cells. Our data thus suggests that elevated levels of HtrA4 in the early-onset PE circulation may impair endothelial cell repair, not only by halting endothelial cell proliferation, but also by inhibiting the proliferation and differentiation of circulating EPCs.
子痫前期（PE）是一种危及生命的妊娠并发症，除了早产之外，没有有效的治疗方法。它的特征是全身性内皮损伤/功能障碍，据信这是由胎盘来源的异常水平/类型的因子在母体血液中循环引起的。新出现的证据表明，PE 中内皮修复也失调，因为对内皮再生至关重要的循环内皮祖细胞（EPC）数量减少且功能受损。然而，其潜在机制尚不清楚。HtrA4 是一种胎盘特异性蛋白酶，分泌到血液循环中，在早发型子痫前期中显著升高。在这里，我们研究了 HtrA4 对内皮细胞增殖和修复的影响。我们证明，高水平的 HtrA4 阻止内皮细胞增殖，并显著下调了许多对细胞周期进展至关重要的基因，包括 CDKN3、BIRC5、CDK1 和 MKI67。此外，HtrA4 还显著抑制了从足月人脐带血中分离出的原代 EPC 的增殖，并阻碍了它们向成熟内皮细胞的分化。因此，我们的数据表明，早发型 PE 循环中高水平的 HtrA4 可能会损害内皮细胞修复，不仅通过阻止内皮细胞增殖，还通过抑制循环 EPC 的增殖和分化。
