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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 <jats:italic>CDKN3<\/jats:italic>, <jats:italic>BIRC5<\/jats:italic>, <jats:italic>CDK1<\/jats:italic> and <jats:italic>MKI67<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1038\/s41598-019-39565-9","type":"journal-article","created":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T11:03:08Z","timestamp":1551092588000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["HtrA4 may play a major role in inhibiting endothelial repair in pregnancy complication preeclampsia"],"prefix":"10.1038","volume":"9","author":[{"given":"Yao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiying","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,25]]},"reference":[{"key":"39565_CR1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/s0140-6736(10)60279-6","volume":"376","author":"EA Steegers","year":"2010","unstructured":"Steegers, E. A., von Dadelszen, P., Duvekot, J. J. & Pijnenborg, R. Pre-eclampsia. Lancet (London, England) 376, 631\u2013644, https:\/\/doi.org\/10.1016\/s0140-6736(10)60279-6 (2010).","journal-title":"Lancet (London, England)"},{"key":"39565_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejogrb.2013.05.005","volume":"170","author":"E Abalos","year":"2013","unstructured":"Abalos, E., Cuesta, C., Grosso, A. L., Chou, D. & Say, L. Global and regional estimates of preeclampsia and eclampsia: a systematic review. European journal of obstetrics, gynecology, and reproductive biology 170, 1\u20137, https:\/\/doi.org\/10.1016\/j.ejogrb.2013.05.005 (2013).","journal-title":"European journal of obstetrics, gynecology, and reproductive biology"},{"key":"39565_CR3","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/S0140-6736(00)03577-7","volume":"357","author":"JM Roberts","year":"2001","unstructured":"Roberts, J. M. & Cooper, D. W. 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