{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:57:45Z","timestamp":1778860665085,"version":"3.51.4"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,6,22]],"date-time":"2018-06-22T00:00:00Z","timestamp":1529625600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The Prematurity Research Fund"},{"name":"March of Dimes Prematurity Research Center at Stanford"},{"name":"Mary L. 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The majority of these macrophages are believed to be alternatively activated macrophages (M2).<\/jats:p><\/jats:sec><jats:sec><jats:title>Method of Study<\/jats:title><jats:p>Mouse bone marrow cells were differentiated into macrophages and polarized to M2 in vitro by treatment with <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20104 [M2a] or <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u201010 [M2c] and M1 with <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">IFN<\/jats:styled-content>\u2010\u03b3 as controls. Macrophage subtypes were confirmed by surface markers and characterized by gene expression profiles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to M1, M2 showed strong pro\u2010angiogenic activity by expressing higher <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> for angiogenic\u2010associated factors (Cxcl12, Vegfa, Pl<jats:styled-content style=\"fixed-case\">GF<\/jats:styled-content>, Mmp2). M2c produced the highest levels of Pl<jats:styled-content style=\"fixed-case\">GF<\/jats:styled-content>, Mmp2, and Cxcr4. To mimic the normal placental microenvironment, M2 were exposed to hypoxia and sex hormones (progesterone, estrogen). In both M2c and M2a, severe hypoxic (1%\u20103% O<jats:sub>2<\/jats:sub>) exposure significantly suppressed Pl<jats:styled-content style=\"fixed-case\">GF<\/jats:styled-content>, Cxcl12, and Mmp2 <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>, but not Vegfa, compared to normoxia (21% O<jats:sub>2<\/jats:sub>) or physiological hypoxia (5% O<jats:sub>2<\/jats:sub>). <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> expression returned to normal when hypoxic cells were returned to normoxia. Hypoxia (1%) reduced antioxidant levels in M2 and re\u2010exposure to normoxia significantly increased superoxide dismutase (Sod1, Sod2) and heme oxygenase\u20101 (<jats:styled-content style=\"fixed-case\">HO<\/jats:styled-content>\u20101) levels in M2a, and only glutathione peroxidase (Gpx1, Gpx3, Gpx4) in M2c. However, progesterone and estrogen treatment had minimal effects on angiogenic factor expression in M2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>M2, particularly M2c, displayed strong pro\u2010angiogenic potential, which decreased under severe hypoxia such as in early pregnancy. Thus, conditions that alter the placental oxygen microenvironment or macrophage response in early pregnancy might cause aberrant angiogenesis and vascular remodeling, and lead to abnormal placental vascular development.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.12989","type":"journal-article","created":{"date-parts":[[2018,6,22]],"date-time":"2018-06-22T11:38:39Z","timestamp":1529667519000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Hypoxia regulates placental angiogenesis via alternatively activated macrophages"],"prefix":"10.1111","volume":"80","author":[{"given":"Hui","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pediatrics Stanford University School of Medicine  Stanford CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flora S.","family":"Kalish","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Stanford University School of 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