HtrA4 may play a major role in inhibiting endothelial repair in pregnancy complication preeclampsia

Yao Wang,Guiying Nie,Rebecca Lim

doi:10.1038/s41598-019-39565-9

Abstract

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.

Highlights

Preeclampsia (PE) is a serious disorder of human pregnancy that affects 2–8% of pregnancies worldwide[1,2]
Endothelial progenitor cells (EPCs) are a unique population of cells that circulate in the blood, and are recruited to the endothelium upon endothelial injury, where they differentiate into resident endothelial cells to regenerate the blood vessels and restore endothelial function[18,19]
We have further demonstrated that elevated concentrations of high temperature requirement factor A4 (HtrA4) detected in early-onset PE circulation disrupt human umbilical vein endothelial cell (HUVEC) tube formation and induce pro-inflammation[36,45]

Summary

Introduction

Preeclampsia (PE) is a serious disorder of human pregnancy that affects 2–8% of pregnancies worldwide[1,2]. The risk of cardiovascular disease is much higher in women who have had early-onset than late-onset PE12–14, suggesting that endothelial dysfunction is more profound in early-onset PE and persists long after the pregnancy[15]. This is consistent with the view that endothelial dysfunction resulting from PE may account for the increased risk of cardiovascular diseases in women with a history of preeclamptic pregnancies[17] Circulating EPCs in early-onset PE are reported to exhibit increased senescence[30] These studies suggest that EPCs may play an important role in normal pregnancy but they are reduced in number and functionality in PE. It is unknown how EPCs are compromised in PE

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