{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:45:14Z","timestamp":1789922714244,"version":"4.0.1"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T00:00:00Z","timestamp":1607385600000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100009633","name":"HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01 HD090066"],"award-info":[{"award-number":["R01 HD090066"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,6,23]]},"abstract":"<jats:p>Implantation is initiated when an embryo attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2\u03b1), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2\u03b1 expression. Further studies revealed that HIF2\u03b1 regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP-9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2\u03b1-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy.<\/jats:p>","DOI":"10.1073\/pnas.2000810117","type":"journal-article","created":{"date-parts":[[2020,6,8]],"date-time":"2020-06-08T20:35:21Z","timestamp":1591648521000},"page":"14532-14542","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":40,"title":["A hypoxia-induced Rab pathway regulates embryo implantation by controlled trafficking of secretory granules"],"prefix":"10.1073","volume":"117","author":[{"given":"Arpita","family":"Bhurke","sequence":"first","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5889-8157","authenticated-orcid":false,"given":"Athilakshmi","family":"Kannan","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Neff","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5140-488X","authenticated-orcid":false,"given":"Mary J.","family":"Laws","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61802"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1423-6351","authenticated-orcid":false,"given":"Robert N.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT 84132"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0371-2463","authenticated-orcid":false,"given":"Milan K.","family":"Bagchi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indrani C.","family":"Bagchi","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61802"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,6,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1055\/s-0029-1242989","article-title":"Endometrial decidualization: Of mice and men","volume":"28","author":"Ramathal C. Y.","year":"2010","unstructured":"C. Y. Ramathal, I. C. Bagchi, R. N. Taylor, M. K. Bagchi, Endometrial decidualization: Of mice and men. Semin. Reprod. Med. 28, 17\u201326 (2010).","journal-title":"Semin. Reprod. Med."},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1210\/me.2014-1074","article-title":"Minireview: Steroid-regulated paracrine mechanisms controlling implantation","volume":"28","author":"Pawar S.","year":"2014","unstructured":"S. Pawar, A. M. Hantak, I. C. Bagchi, M. K. Bagchi, Minireview: Steroid-regulated paracrine mechanisms controlling implantation. Mol. Endocrinol. 28, 1408\u20131422 (2014).","journal-title":"Mol. Endocrinol."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.semcdb.2013.08.004","article-title":"Role of nuclear receptors in blastocyst implantation","volume":"24","author":"Vasquez Y. M.","year":"2013","unstructured":"Y. M. Vasquez, F. J. DeMayo, Role of nuclear receptors in blastocyst implantation. Semin. Cell Dev. Biol. 24, 724\u2013735 (2013).","journal-title":"Semin. Cell Dev. Biol."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.mam.2012.12.011","article-title":"Physiological and molecular determinants of embryo implantation","volume":"34","author":"Zhang S.","year":"2013","unstructured":"S. Zhang ., Physiological and molecular determinants of embryo implantation. Mol. Aspects Med. 34, 939\u2013980 (2013).","journal-title":"Mol. Aspects Med."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1387\/ijdb.130348mb","article-title":"Role of uterine stromal-epithelial crosstalk in embryo implantation","volume":"58","author":"Hantak A. M.","year":"2014","unstructured":"A. M. Hantak, I. C. Bagchi, M. K. Bagchi, Role of uterine stromal-epithelial crosstalk in embryo implantation. Int. J. Dev. Biol. 58, 139\u2013146 (2014).","journal-title":"Int. J. Dev. Biol."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1172\/JCI200422991","article-title":"Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface","volume":"114","author":"Red-Horse K.","year":"2004","unstructured":"K. Red-Horse ., Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J. Clin. Invest. 114, 744\u2013754 (2004).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S1521-6934(02)00130-X","article-title":"The endometrium as a cause of implantation failure","volume":"17","author":"Sharkey A. M.","year":"2003","unstructured":"A. M. Sharkey, S. K. Smith, The endometrium as a cause of implantation failure. Best Pract. Res. Clin. Obstet. Gynaecol. 17, 289\u2013307 (2003).","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S1472-6483(10)60649-9","article-title":"Defective implantation and placentation: Laying the blueprint for pregnancy complications","volume":"13","author":"Norwitz E. R.","year":"2006","unstructured":"E. R. Norwitz, Defective implantation and placentation: Laying the blueprint for pregnancy complications. Reprod. Biomed. Online 13, 591\u2013599 (2006).","journal-title":"Reprod. Biomed. Online"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1097\/GCO.0b013e3283404e44","article-title":"Obstetric outcome after early placental complications","volume":"22","author":"Jauniaux E.","year":"2010","unstructured":"E. Jauniaux, R. H. Van Oppenraaij, G. J. Burton, Obstetric outcome after early placental complications. Curr. Opin. Obstet. Gynecol. 22, 452\u2013457 (2010).","journal-title":"Curr. Opin. Obstet. Gynecol."},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1126\/science.7985020","article-title":"Implantation and the placenta: Key pieces of the development puzzle","volume":"266","author":"Cross J. C.","year":"1994","unstructured":"J. C. Cross, Z. Werb, S. J. Fisher, Implantation and the placenta: Key pieces of the development puzzle. Science 266, 1508\u20131518 (1994).","journal-title":"Science"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nrg1808","article-title":"Roadmap to embryo implantation: Clues from mouse models","volume":"7","author":"Wang H.","year":"2006","unstructured":"H. Wang, S. K. Dey, Roadmap to embryo implantation: Clues from mouse models. Nat. Rev. Genet. 7, 185\u2013199 (2006).","journal-title":"Nat. Rev. Genet."},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1038\/nm.3012","article-title":"Mechanisms of implantation: Strategies for successful pregnancy","volume":"18","author":"Cha J.","year":"2012","unstructured":"J. Cha, X. Sun, S. K. Dey, Mechanisms of implantation: Strategies for successful pregnancy. Nat. Med. 18, 1754\u20131767 (2012).","journal-title":"Nat. Med."},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc3183","article-title":"HIF1\u03b1 and HIF2\u03b1: Sibling rivalry in hypoxic tumour growth and progression","volume":"12","author":"Keith B.","year":"2011","unstructured":"B. Keith, R. S. Johnson, M. C. Simon, HIF1\u03b1 and HIF2\u03b1: Sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12, 9\u201322 (2011).","journal-title":"Nat. Rev. Cancer"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"7683","DOI":"10.1074\/jbc.M211390200","article-title":"Expression of hypoxia-inducible factors in the peri-implantation mouse uterus is regulated in a cell-specific and ovarian steroid hormone-dependent manner. Evidence for differential function of HIFs during early pregnancy","volume":"278","author":"Daikoku T.","year":"2003","unstructured":"T. Daikoku ., Expression of hypoxia-inducible factors in the peri-implantation mouse uterus is regulated in a cell-specific and ovarian steroid hormone-dependent manner. Evidence for differential function of HIFs during early pregnancy. J. Biol. Chem. 278, 7683\u20137691 (2003).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1101\/gad.853700a","article-title":"Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses","volume":"14","author":"Adelman D. M.","year":"2000","unstructured":"D. M. Adelman, M. Gertsenstein, A. Nagy, M. C. Simon, E. Maltepe, Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev. 14, 3191\u20133203 (2000).","journal-title":"Genes Dev."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.ydbio.2007.12.007","article-title":"Maternal hypoxia activates endovascular trophoblast cell invasion","volume":"314","author":"Rosario G. X.","year":"2008","unstructured":"G. X. Rosario, T. Konno, M. J. Soares, Maternal hypoxia activates endovascular trophoblast cell invasion. Dev. Biol. 314, 362\u2013375 (2008).","journal-title":"Dev. Biol."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1146\/annurev.physiol.62.1.353","article-title":"Diapause","volume":"62","author":"Renfree M. B.","year":"2000","unstructured":"M. B. Renfree, G. Shaw, Diapause. Annu. Rev. Physiol. 62, 353\u2013375 (2000).","journal-title":"Annu. Rev. Physiol."},{"key":"e_1_3_4_18_2","first-page":"141","article-title":"Molecular and cellular aspects of facultative delayed implantation in the mouse","author":"Van Blerkom J.","year":"1978","unstructured":"J. Van Blerkom, D. J. Chavez, H. Bell, Molecular and cellular aspects of facultative delayed implantation in the mouse. Ciba Found. Symp., 141\u2013172 (1978).","journal-title":"Ciba Found. Symp."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1530\/jrf.0.0120593","article-title":"Delayed implantation in the spayed, progesterone treated adult mouse","volume":"12","author":"Yoshinaga K.","year":"1966","unstructured":"K. Yoshinaga, C. E. Adams, Delayed implantation in the spayed, progesterone treated adult mouse. J. Reprod. Fertil. 12, 593\u2013595 (1966).","journal-title":"J. Reprod. Fertil."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"e1002500","DOI":"10.1371\/journal.pgen.1002500","article-title":"Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium","volume":"8","author":"Nallasamy S.","year":"2012","unstructured":"S. Nallasamy, Q. Li, M. K. Bagchi, I. C. Bagchi, Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium. PLoS Genet. 8, e1002500 (2012).","journal-title":"PLoS Genet."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1126\/science.1197454","article-title":"The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2","volume":"331","author":"Li Q.","year":"2011","unstructured":"Q. Li ., The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science 331, 912\u2013916 (2011).","journal-title":"Science"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1210\/en.2006-1394","article-title":"Estrogen-induced activation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3-kinase\/Akt pathway","volume":"148","author":"Kazi A. A.","year":"2007","unstructured":"A. A. Kazi, R. D. Koos, Estrogen-induced activation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3-kinase\/Akt pathway. Endocrinology 148, 2363\u20132374 (2007).","journal-title":"Endocrinology"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ar.1092430105","article-title":"Loss of laminin and type IV collagen in uterine luminal epithelial basement membranes during blastocyst implantation in the mouse","volume":"243","author":"Blankenship T. N.","year":"1995","unstructured":"T. N. Blankenship, R. L. Given, Loss of laminin and type IV collagen in uterine luminal epithelial basement membranes during blastocyst implantation in the mouse. Anat. Rec. 243, 27\u201336 (1995).","journal-title":"Anat. Rec."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1210\/me.2013-1206","article-title":"STAT3 regulates uterine epithelial remodeling and epithelial-stromal crosstalk during implantation","volume":"27","author":"Pawar S.","year":"2013","unstructured":"S. Pawar ., STAT3 regulates uterine epithelial remodeling and epithelial-stromal crosstalk during implantation. Mol. Endocrinol. 27, 1996\u20132012 (2013).","journal-title":"Mol. Endocrinol."},{"key":"e_1_3_4_25_2","first-page":"389","article-title":"Epithelial cell polarity and embryo implantation in mammals","volume":"40","author":"Thie M.","year":"1996","unstructured":"M. Thie, P. Fuchs, H. W. Denker, Epithelial cell polarity and embryo implantation in mammals. Int. J. Dev. Biol. 40, 389\u2013393 (1996).","journal-title":"Int. J. Dev. Biol."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1093\/humrep\/11.suppl_2.124","article-title":"Matrix metalloproteinases in normal menstruation","volume":"11","author":"Salamonsen L. A.","year":"1996","unstructured":"L. A. Salamonsen, D. E. Woolley, Matrix metalloproteinases in normal menstruation. Hum. Reprod. 11 (suppl. 2), 124\u2013133 (1996).","journal-title":"Hum. Reprod."},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1530\/ror.0.0040011","article-title":"Role of proteases in implantation","volume":"4","author":"Salamonsen L. A.","year":"1999","unstructured":"L. A. Salamonsen, Role of proteases in implantation. Rev. Reprod. 4, 11\u201322 (1999).","journal-title":"Rev. Reprod."},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1530\/jrf.0.1200125","article-title":"Expression of matrix metalloproteinases 2 and 9 in the mouse uterus during implantation and oil-induced decidualization","volume":"120","author":"Bany B. M.","year":"2000","unstructured":"B. M. Bany, M. B. Harvey, G. A. Schultz, Expression of matrix metalloproteinases 2 and 9 in the mouse uterus during implantation and oil-induced decidualization. J. Reprod. Fertil. 120, 125\u2013134 (2000).","journal-title":"J. Reprod. Fertil."},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1530\/jrf.0.0450463","article-title":"Epithelial cell death in the oil-induced decidual reaction of the pseudopregnant mouse: An ultrastructural study","volume":"45","author":"Hinchliffe J. R.","year":"1975","unstructured":"J. R. Hinchliffe, A. M. El-Shershaby, Epithelial cell death in the oil-induced decidual reaction of the pseudopregnant mouse: An ultrastructural study. J. Reprod. Fertil. 45, 463\u2013468 (1975).","journal-title":"J. Reprod. Fertil."},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1242\/dev.122.6.1723","article-title":"Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation","volume":"122","author":"Alexander C. M.","year":"1996","unstructured":"C. M. Alexander ., Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. Development 122, 1723\u20131736 (1996).","journal-title":"Development"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"649","DOI":"10.2741\/2089","article-title":"The matrix metalloproteinases (MMPS) in the decidua and fetal membranes","volume":"12","author":"Weiss A.","year":"2007","unstructured":"A. Weiss, S. Goldman, E. Shalev, The matrix metalloproteinases (MMPS) in the decidua and fetal membranes. Front. Biosci. 12, 649\u2013659 (2007).","journal-title":"Front. Biosci."},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1699-0463.1999.tb01524.x","article-title":"Mechanisms for pro matrix metalloproteinase activation","volume":"107","author":"Murphy G.","year":"1999","unstructured":"G. Murphy ., Mechanisms for pro matrix metalloproteinase activation. APMIS 107, 38\u201344 (1999).","journal-title":"APMIS"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/nm.2153","article-title":"Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction","volume":"16","author":"Yang S.","year":"2010","unstructured":"S. Yang ., Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat. Med. 16, 687\u2013693 (2010).","journal-title":"Nat. Med."},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1091\/mbc.e07-05-0409","article-title":"Rab27b is expressed in a wide range of exocytic cells and involved in the delivery of secretory granules near the plasma membrane","volume":"18","author":"Gomi H.","year":"2007","unstructured":"H. Gomi, K. Mori, S. Itohara, T. Izumi, Rab27b is expressed in a wide range of exocytic cells and involved in the delivery of secretory granules near the plasma membrane. Mol. Biol. Cell 18, 4377\u20134386 (2007).","journal-title":"Mol. Biol. Cell"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"5872","DOI":"10.1073\/pnas.0609879104","article-title":"Rab27b regulates number and secretion of platelet dense granules","volume":"104","author":"Tolmachova T.","year":"2007","unstructured":"T. Tolmachova, M. Abrink, C. E. Futter, K. S. Authi, M. C. Seabra, Rab27b regulates number and secretion of platelet dense granules. Proc. Natl. Acad. Sci. U.S.A. 104, 5872\u20135877 (2007).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"3444","DOI":"10.1182\/blood-2007-10-116285","article-title":"The tetraspanin CD63 is involved in granule targeting of neutrophil elastase","volume":"112","author":"K\u00e4llquist L.","year":"2008","unstructured":"L. K\u00e4llquist ., The tetraspanin CD63 is involved in granule targeting of neutrophil elastase. Blood 112, 3444\u20133454 (2008).","journal-title":"Blood"},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1189\/jlb.3A1015-480R","article-title":"CD63 is tightly associated with intracellular, secretory events chaperoning piecemeal degranulation and compound exocytosis in human eosinophils","volume":"100","author":"Carmo L. A.","year":"2016","unstructured":"L. A. Carmo ., CD63 is tightly associated with intracellular, secretory events chaperoning piecemeal degranulation and compound exocytosis in human eosinophils. J. Leukoc. Biol. 100, 391\u2013401 (2016).","journal-title":"J. Leukoc. Biol."},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1210\/endo.138.6.5155","article-title":"Decidual\/trophoblast prolactin-related protein: Characterization of gene structure and cell-specific expression","volume":"138","author":"Orwig K. E.","year":"1997","unstructured":"K. E. Orwig, G. Dai, C. A. Rasmussen, M. J. Soares, Decidual\/trophoblast prolactin-related protein: Characterization of gene structure and cell-specific expression. Endocrinology 138, 2491\u20132500 (1997).","journal-title":"Endocrinology"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1095\/biolreprod58.2.273","article-title":"The uteroplacental prolactin family and pregnancy","volume":"58","author":"Soares M. J.","year":"1998","unstructured":"M. J. Soares, H. M\u00fcller, K. E. Orwig, T. J. Peters, G. Dai, The uteroplacental prolactin family and pregnancy. Biol. Reprod. 58, 273\u2013284 (1998).","journal-title":"Biol. Reprod."},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1530\/jrf.0.0080331","article-title":"Reaction of the mouse uterus during implantation and deciduoma formation as demonstrated by changes in the distribution of alkaline phosphatase","volume":"8","author":"Finn C. A.","year":"1964","unstructured":"C. A. Finn, J. R. Hinchliffe, Reaction of the mouse uterus during implantation and deciduoma formation as demonstrated by changes in the distribution of alkaline phosphatase. J. Reprod. Fertil. 8, 331\u2013338 (1964).","journal-title":"J. Reprod. Fertil."},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"31725","DOI":"10.1074\/jbc.M704723200","article-title":"Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human","volume":"282","author":"Li Q.","year":"2007","unstructured":"Q. Li ., Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J. Biol. Chem. 282, 31725\u201331732 (2007).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1242\/dev.019810","article-title":"Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival","volume":"135","author":"Laws M. J.","year":"2008","unstructured":"M. J. Laws ., Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development 135, 2659\u20132668 (2008).","journal-title":"Development"},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1128\/MCB.00342-07","article-title":"Bmp2 is critical for the murine uterine decidual response","volume":"27","author":"Lee K. Y.","year":"2007","unstructured":"K. Y. Lee ., Bmp2 is critical for the murine uterine decidual response. Mol. Cell. Biol. 27, 5468\u20135478 (2007).","journal-title":"Mol. Cell. Biol."},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1101\/gad.9.18.2266","article-title":"Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities","volume":"9","author":"Lydon J. P.","year":"1995","unstructured":"J. P. Lydon ., Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 9, 2266\u20132278 (1995).","journal-title":"Genes Dev."},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1210\/endo.133.5.8404671","article-title":"Cyclic adenosine 3\u2032,5\u2032-monophosphate induces prolactin expression in stromal cells isolated from human proliferative endometrium","volume":"133","author":"Tang B.","year":"1993","unstructured":"B. Tang, S. Guller, E. Gurpide, Cyclic adenosine 3\u2032,5\u2032-monophosphate induces prolactin expression in stromal cells isolated from human proliferative endometrium. Endocrinology 133, 2197\u20132203 (1993).","journal-title":"Endocrinology"},{"key":"e_1_3_4_46_2","first-page":"642","article-title":"Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro","volume":"78","author":"Ryan I. P.","year":"1994","unstructured":"I. P. Ryan, E. D. Schriock, R. N. Taylor, Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J. Clin. Endocrinol. Metab. 78, 642\u2013649 (1994).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","first-page":"e1005458","DOI":"10.1371\/journal.pgen.1005458","article-title":"Rac1 regulates endometrial secretory function to control placental development","volume":"11","author":"Davila J.","year":"2015","unstructured":"J. Davila ., Rac1 regulates endometrial secretory function to control placental development. PLoS Genet. 11, e1005458 (2015).","journal-title":"PLoS Genet."},{"key":"e_1_3_4_48_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/jez.1402060108","article-title":"The effect of oxygen on the development of preimplantation mouse embryos in vitro","volume":"206","author":"Quinn P.","year":"1978","unstructured":"P. Quinn, G. M. Harlow, The effect of oxygen on the development of preimplantation mouse embryos in vitro. J. Exp. Zool. 206, 73\u201380 (1978).","journal-title":"J. Exp. Zool."},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1210\/endo-83-4-691","article-title":"Measurement of intrauterine oxygen tension in the rat and its regulation by ovarian steroid hormones","volume":"83","author":"Mitchell J. A.","year":"1968","unstructured":"J. A. Mitchell, J. M. Yochim, Measurement of intrauterine oxygen tension in the rat and its regulation by ovarian steroid hormones. Endocrinology 83, 691\u2013700 (1968).","journal-title":"Endocrinology"},{"key":"e_1_3_4_50_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.anireprosci.2006.10.008","article-title":"The role of oxygen in ruminant preimplantation embryo development and metabolism","volume":"98","author":"Harvey A. J.","year":"2007","unstructured":"A. J. Harvey, The role of oxygen in ruminant preimplantation embryo development and metabolism. Anim. Reprod. Sci. 98, 113\u2013128 (2007).","journal-title":"Anim. Reprod. Sci."},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2217\/17460751.1.1.71","article-title":"Oxygen, epigenetics and stem cell fate","volume":"1","author":"Okazaki K.","year":"2006","unstructured":"K. Okazaki, E. Maltepe, Oxygen, epigenetics and stem cell fate. Regen. Med. 1, 71\u201383 (2006).","journal-title":"Regen. Med."},{"key":"e_1_3_4_52_2","first-page":"283","article-title":"Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy","volume":"80","author":"Rodesch F.","year":"1992","unstructured":"F. Rodesch, P. Simon, C. Donner, E. Jauniaux, Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet. Gynecol. 80, 283\u2013285 (1992).","journal-title":"Obstet. Gynecol."},{"key":"e_1_3_4_53_2","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1093\/humrep\/del212","article-title":"The effects of oxygen concentration and gestational age on extravillous trophoblast outgrowth in a human first trimester villous explant model","volume":"21","author":"James J. L.","year":"2006","unstructured":"J. L. James, P. R. Stone, L. W. Chamley, The effects of oxygen concentration and gestational age on extravillous trophoblast outgrowth in a human first trimester villous explant model. Hum. Reprod. 21, 2699\u20132705 (2006).","journal-title":"Hum. Reprod."},{"key":"e_1_3_4_54_2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41467-017-02375-6","article-title":"Hypoxia and hypoxia inducible factor-1\u03b1 are required for normal endometrial repair during menstruation","volume":"9","author":"Maybin J. A.","year":"2018","unstructured":"J. A. Maybin ., Hypoxia and hypoxia inducible factor-1\u03b1 are required for normal endometrial repair during menstruation. Nat. Commun. 9, 295 (2018).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_55_2","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1158\/0008-5472.CAN-06-2808","article-title":"Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells","volume":"67","author":"Symowicz J.","year":"2007","unstructured":"J. Symowicz ., Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res. 67, 2030\u20132039 (2007).","journal-title":"Cancer Res."},{"key":"e_1_3_4_56_2","doi-asserted-by":"crossref","first-page":"19622","DOI":"10.1074\/jbc.M111.297663","article-title":"Estrogen-induced expression of Fos-related antigen 1 (FRA-1) regulates uterine stromal differentiation and remodeling","volume":"287","author":"Das A.","year":"2012","unstructured":"A. Das ., Estrogen-induced expression of Fos-related antigen 1 (FRA-1) regulates uterine stromal differentiation and remodeling. J. Biol. Chem. 287, 19622\u201319630 (2012).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_57_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yexcr.2014.07.027","article-title":"Rab proteins: The key regulators of intracellular vesicle transport","volume":"328","author":"Bhuin T.","year":"2014","unstructured":"T. Bhuin, J. K. Roy, Rab proteins: The key regulators of intracellular vesicle transport. Exp. Cell Res. 328, 1\u201319 (2014).","journal-title":"Exp. Cell Res."},{"key":"e_1_3_4_58_2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1083\/jcb.201306010","article-title":"Review series: Rab GTPases and membrane identity: Causal or inconsequential?","volume":"202","author":"Barr F. A.","year":"2013","unstructured":"F. A. Barr, Review series: Rab GTPases and membrane identity: Causal or inconsequential? J. Cell Biol. 202, 191\u2013199 (2013).","journal-title":"J. Cell Biol."},{"key":"e_1_3_4_59_2","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1152\/physrev.00031.2002","article-title":"Secretory granule exocytosis","volume":"83","author":"Burgoyne R. D.","year":"2003","unstructured":"R. D. Burgoyne, A. Morgan, Secretory granule exocytosis. Physiol. Rev. 83, 581\u2013632 (2003).","journal-title":"Physiol. Rev."},{"key":"e_1_3_4_60_2","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.3892\/or.2015.4125","article-title":"Hypomethylated Rab27b is a progression-associated prognostic biomarker of glioma regulating MMP-9 to promote invasion","volume":"34","author":"Wang H.","year":"2015","unstructured":"H. Wang ., Hypomethylated Rab27b is a progression-associated prognostic biomarker of glioma regulating MMP-9 to promote invasion. Oncol. Rep. 34, 1503\u20131509 (2015).","journal-title":"Oncol. Rep."},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/oxfordjournals.humrep.a138492","article-title":"Decidualization of human endometrial stromal cells in vitro: Effects of progestin and relaxin on the ultrastructure and production of decidual secretory proteins","volume":"9","author":"Lane B.","year":"1994","unstructured":"B. Lane, W. Oxberry, J. Mazella, L. Tseng, Decidualization of human endometrial stromal cells in vitro: Effects of progestin and relaxin on the ultrastructure and production of decidual secretory proteins. Hum. Reprod. 9, 259\u2013266 (1994).","journal-title":"Hum. Reprod."},{"key":"e_1_3_4_62_2","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/S0006-291X(03)00544-8","article-title":"Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase","volume":"304","author":"Takino T.","year":"2003","unstructured":"T. Takino ., Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase. Biochem. Biophys. Res. Commun. 304, 160\u2013166 (2003).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"e_1_3_4_63_2","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.1172\/JCI98931","article-title":"HIF2\u03b1 in the uterine stroma permits embryo invasion and luminal epithelium detachment","volume":"128","author":"Matsumoto L.","year":"2018","unstructured":"L. Matsumoto ., HIF2\u03b1 in the uterine stroma permits embryo invasion and luminal epithelium detachment. J. Clin. Invest. 128, 3186\u20133197 (2018).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_64_2","doi-asserted-by":"crossref","first-page":"11459","DOI":"10.1073\/pnas.1002443107","article-title":"Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders","volume":"107","author":"Beall C. M.","year":"2010","unstructured":"C. M. Beall ., Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc. Natl. Acad. Sci. U.S.A. 107, 11459\u201311464 (2010).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_65_2","doi-asserted-by":"crossref","first-page":"e0186149","DOI":"10.1371\/journal.pone.0186149","article-title":"Novel genes and mutations in patients affected by recurrent pregnancy loss","volume":"12","author":"Quintero-Ronderos P.","year":"2017","unstructured":"P. Quintero-Ronderos ., Novel genes and mutations in patients affected by recurrent pregnancy loss. PLoS One 12, e0186149 (2017).","journal-title":"PLoS One"},{"key":"e_1_3_4_66_2","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/molehr\/6.3.276","article-title":"VEGF, its receptors and the tie receptors in recurrent miscarriage","volume":"6","author":"Vuorela P.","year":"2000","unstructured":"P. Vuorela, O. Carp\u00e9n, M. Tulppala, E. Halmesm\u00e4ki, VEGF, its receptors and the tie receptors in recurrent miscarriage. Mol. Hum. Reprod. 6, 276\u2013282 (2000).","journal-title":"Mol. Hum. Reprod."},{"key":"e_1_3_4_67_2","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/gene.20098","article-title":"Cre-mediated recombination in cell lineages that express the progesterone receptor","volume":"41","author":"Soyal S. M.","year":"2005","unstructured":"S. M. Soyal ., Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis 41, 58\u201366 (2005).","journal-title":"Genesis"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.2000810117","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2000810117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T17:42:04Z","timestamp":1654623724000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2000810117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,8]]},"references-count":67,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2020,6,23]]}},"alternative-id":["10.1073\/pnas.2000810117"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2000810117","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,8]]},"assertion":[{"value":"2020-06-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}