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Inflammatory activation of the complement cascade has also been thought to be a contributory factor to PE pathophysiology. However, the placental and circulating presence of activated complement factors and their precise impact on gestational age\u2010dependent trophoblast health remain inadequately addressed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method of Study<\/jats:title><jats:p>Complement activation was assessed in placental tissue samples from women with normal pregnancy (NP) and PE. Immunofluorescent staining was employed to detect the membrane attack complex (MAC) deposition in placental tissues. This approach was also used in placenta\u2010derived human extravillous trophoblast cells derived from the third trimester (TCL1) and first trimester (HTR\u20108) and term primary human cytotrophoblasts. Dual staining with Propidium Iodide (PI) and annexin V antibody was conducted to assess cell viability in TCL\u20101 cells, HTR\u20108 cells, and freshly isolated term primary human trophoblasts when exposed to serum samples from NP (NPS), PE (PES), and PES after complement inactivation by heating, heparin treatment, or blockade with antibodies. The expression levels of complement regulatory proteins, specifically decay\u2010accelerating factor (CD55), protectin (CD59), and membrane cofactor protein (CD46), on trophoblasts were quantified using Fluorescence\u2010activated cell sorting and immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Substantial MAC deposition and a notable reduction in CD55 expression in the PE placenta compared to that from NP was observed, indicating heightened complement activation and impaired complement regulation in PE. Exposure to a significant subpopulation of PES (41%, <jats:italic>n<\/jats:italic> = 41) induced cell death exclusively in TCL\u20101 cells, not in HTR\u20108 cells and primary human trophoblasts. Remarkably, complement inactivation in PES abolished MAC deposition and rescued TCL\u20101 cells from death, unequivocally implicating complement activity in trophoblast cell demise. Flow cytometry analysis disclosed lower levels of CD55 and CD59 expression in TCL\u20101 cells in contrast to HTR\u20108 cells and primary human trophoblasts. Blockade of CD55 and CD59 in HTR\u20108 cells enhanced their susceptibility to PES\u2010induced cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings underscore the significance of amplified complement activation, compromised complement inhibitory regulation, and consequent trophoblast cell death as potential contributors to the pathogenesis of PE. Strategies targeting dysregulated complement activity offer promising avenues for novel therapeutic interventions in PE management.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.70076","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T15:14:18Z","timestamp":1747667658000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Evidence for Complement Activation in Preeclampsia Placenta and Its Presence in Circulation"],"prefix":"10.1111","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4911-6234","authenticated-orcid":false,"given":"Shibin","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Pediatrics Warren Alpert Medical School of Brown University  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Norris","sequence":"additional","affiliation":[{"name":"Women and Infants Hospital  Providence 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