{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T04:18:10Z","timestamp":1792815490775,"version":"4.5.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,6,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Preeclampsia is a placenta-origin pregnancy complication. Although its development has long been divided into 2 stages: abnormal placentation (stage I) and the release of factors from the hypoperfused placenta into circulation, triggering preeclampsia due to endothelial dysfunction (stage II), the placenta-derived substances coupling the 2 stages remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Extracellular vesicles (EVs) from normal and preeclampsia-complicated placentas were intravenously administered to pregnant mice, and blood pressure was recorded throughout pregnancy. The differential cargo, including NEP (neprilysin), of placental EVs in normal and preeclamptic placentas was identified by liquid chromatography-mass spectrometry, and the cell types involved in NEP expression in the placenta were determined by single-cell RNA sequencing. The effects of placental EVs and recombinant mouse NEP on the uterine arteries were assessed by myography. Placenta-specific NEP overexpression mice were established by in situ injection of adenovirus. The binding affinity between NEP and the vasodilative peptides was determined using an Octet instrument. NEP-overexpressing human umbilical vein endothelial cells were established to measure CNP (C-type natriuretic peptide) release and cocultured with NPRB (natriuretic peptide receptor-B) knockdown vascular smooth muscle cells (VSMCs) to measure cGMP production in VSMCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Placental EVs from preeclamptic pregnancies impaired vascular endothelium\u2013dependent vasodilation and induced preeclampsia in mice. NEP was expressed predominantly by syncytiotrophoblasts and upregulated in placental EVs from preeclamptic pregnancies. Recombinant mouse NEP administration resulted in outcomes like those of administration of placental EVs from preeclamptic pregnancies. Placenta-specific NEP overexpression disturbed maternal hemodynamics, resulting in hypertension and proteinuria of the mice. CNP exhibited high binding affinity for NEP, and NEP upregulation in human umbilical vein endothelial cells inhibited CNP release, which further influenced the production of cGMP in VSMCs; however, this effect was largely blunted in NPRB-deficient VSMCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Excessive NEP in placental EVs from preeclamptic pregnancies is transported into the endothelial cells of uterine and placental arteries to cleave and degrade CNP, resulting in compromised CNP paracrine activity and NPRB-mediated cGMP production in adjacent VSMCs and triggering the hypertensive manifestation of preeclampsia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.124.325673","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T05:00:13Z","timestamp":1745989213000},"page":"1526-1541","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Excess Neprilysin in Placental EVs Impairs CNP-NPRB-Mediated Vasodilation to Trigger Preeclamptic Hypertension"],"prefix":"10.1161","volume":"136","author":[{"given":"Chengjin","family":"He","sequence":"first","affiliation":[{"name":"State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (C.H., Y.D., J.H., Y.F., H.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (C.H., Y.D., J.H., Y.F., H.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University (R.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, China (Y.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (C.H., Y.D., J.H., Y.F., H.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Women and Children\u2019s Hospital of Chongqing Medical University, China (L.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-4223","authenticated-orcid":true,"given":"Mark D.","family":"Kilby","sequence":"additional","affiliation":[{"name":"Fetal Medicine Centre, Birmingham Women\u2019s and Children\u2019s Foundation Trust, United Kingdom (M.D.K.)."},{"name":"College of Medical and Health Sciences, University of Birmingham, United Kingdom (M.D.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (C.H., Y.D., J.H., Y.F., H.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Qi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, China (C.H., Y.D., J.H., Y.F., H.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4592-6427","authenticated-orcid":true,"given":"Philip N.","family":"Baker","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park, United Kingdom (P.N.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0828-2674","authenticated-orcid":true,"given":"Chao","family":"Tong","sequence":"additional","affiliation":[{"name":"Growth, Development and Mental Health Center of Children and Adolescents, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children\u2019s Hospital of Chongqing Medical University, China 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