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Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor runt-related transcription factor 1 (RUNX1) in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrate that RUNX1 regulates the conserved hypoxia-inducible factor 2 \u03b1-RAB27B pathway in primary human endometrial stromal cells (HESCs) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including angiopoietin-related protein 2 (ANGPTL2) and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.<\/jats:p>","DOI":"10.1210\/endocr\/bqaf133","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T10:11:59Z","timestamp":1756462319000},"source":"Crossref","is-referenced-by-count":5,"title":["Human Decidual RUNX1 Promotes Angiogenesis and Trophoblast Differentiation by Regulating Extracellular Vesicle Signaling"],"prefix":"10.1210","volume":"166","author":[{"given":"Jacob R","family":"Beal","sequence":"first","affiliation":[{"name":"Departments of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign , Urbana, IL 61801 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangning","family":"Song","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign , Urbana, IL 61801 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5889-8157","authenticated-orcid":false,"given":"Athilakshmi","family":"Kannan","sequence":"additional","affiliation":[{"name":"Comparative Biosciences, University of Illinois, Urbana-Champaign , Urbana, IL 61801 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University at Buffalo , Buffalo, NY 14203 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6032-2632","authenticated-orcid":false,"given":"Indrani C","family":"Bagchi","sequence":"additional","affiliation":[{"name":"Comparative Biosciences, University of Illinois, Urbana-Champaign , Urbana, IL 61801 ,","place":["USA"]}],"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":"Departments of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign , Urbana, IL 61801 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"issue":"21","key":"2025092506363975700_bqaf133-B1","doi-asserted-by":"crossref","first-page":"10159","DOI":"10.1073\/pnas.90.21.10159","article-title":"Blastocyst's state of activity determines the \u201cwindow\u201d of implantation in the receptive mouse uterus","volume":"90","author":"Paria","year":"1993","journal-title":"Proc Natl Acad Sci U S 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