{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:26:53Z","timestamp":1785929213190,"version":"3.56.0"},"reference-count":25,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T00:00:00Z","timestamp":1650240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002367","name":"Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["FIRMA200504"],"award-info":[{"award-number":["FIRMA200504"]}],"id":[{"id":"10.13039\/501100002367","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>During early pregnancy, a large number of CD56<jats:sup>bright<\/jats:sup> natural killer cells (NKs) are accumulated in the decidua; unlike peripheral and cord blood NK cells (pNK and cNK), these decidual NK cells (dNK) display a great capacity to secrete a series of angiogenic\/vascular factors, which are essential for placental development. However, the mechanism underlying the formation of dNK cells with an angiogenic phenotype remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>First, we compared the difference between dNK and cNK\/pNK cells in terms of the expression of CD56 and VEGF, and the regulation of the tube formation. The effect of cAMP on the differentiation of NK cells was evaluated by its analog and inhibitor stimulation. We further analyzed the differences in the phenotype of dNK cells and the expression of VEGF in dNK cells from normal pregnancies and miscarriages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Different from cNK and pNK, dNK cells displayed high expression of CD56 and VEGF. And dNK cells showed a higher capacity of inducing tube formation of HUVEC by trophoblast. Meanwhile, we observed that\u00a0cAMP\u2010analogue increased the percentage of CD56<jats:sup>bright<\/jats:sup>NK population in cNK cells with up\u2010regulated VEGF secretion and tube formation of HUVEC by trophoblast, which could be inhibited by pretreatment with VEGFR neutralizing antibody. Similar changes occurred when co\u2010culturing cNK cells with DSCs but not ESCs. Interestingly, the inhibitor of cAMP signaling (Metadoxine, META) could significantly inhibit the upregulation of VEGF in cNK cells by DSCs. Furthermore, DSCs could secret much more cAMP than ESCs. Notably, decreased CD56<jats:sup>bright<\/jats:sup>NK population and VEGF secretion by dNK were related to pregnancy loss.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings suggest that dNK cells display an angiogenic phenotype that can be induced by decidualized cAMP signaling. Our study indicates the significance of decidualization\u2010derived cAMP in regulating angiogenesis of decidual NKs and reveals complex crosstalk between different cell types in a critical period during early pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.13540","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T11:19:56Z","timestamp":1648552796000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Decidualization\u2010derived cAMP promotes decidual NK cells to be angiogenic phenotype"],"prefix":"10.1111","volume":"88","author":[{"given":"Xueling","family":"Jin","sequence":"first","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research) Hospital of Obstetrics and Gynecology Fudan University Shanghai Medical College  Shanghai China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases  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