{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:46:10Z","timestamp":1792107970260,"version":"4.4.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81403321"],"award-info":[{"award-number":["81403321"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Project of Jiangsu Provincial Administration of Traditional Chinese Medicine","award":["MS2023039"],"award-info":[{"award-number":["MS2023039"]}]},{"name":"Science and Technology Project of Jiangsu Provincial Administration of Traditional Chinese Medicine","award":["ZD202419"],"award-info":[{"award-number":["ZD202419"]}]},{"name":"Jiangsu Chinese Medicine Society","award":["CYTF2024025"],"award-info":[{"award-number":["CYTF2024025"]}]},{"name":"Research Project Funding from Affiliated Jiangning Hospital of Chinese Medicine, China Pharmaceutical University","award":["YJZD2025001"],"award-info":[{"award-number":["YJZD2025001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Adenomyosis (AM) is a benign gynecological disorder characterized by the presence of endometrial tissue within the myometrium and is commonly associated with dysmenorrhea and menorrhagia. Although angiogenesis is considered a key process in its pathogenesis, the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the role of the hypoxia-inducible factor 1-alpha (HIF-1\u03b1)\/vascular endothelial growth factor (VEGF) axis in AM. Immunohistochemical analysis revealed that the expression levels of HIF-1\u03b1 and VEGF, as well as microvessel density (MVD), were significantly increased in the eutopic endometrium of patients with AM, with significant positive correlations among these parameters. Paired analysis further showed that adenomyotic lesion tissues exhibited stronger HIF-1\u03b1 and VEGF expression and higher MVD than matched eutopic endometrium. In vitro, using adenomyosis-derived eutopic endometrial stromal cells under cobalt chloride-induced hypoxic conditions, we found that estrogen further enhanced HIF-1\u03b1 and VEGF expression. Mechanistically, estrogen promoted angiogenesis through two distinct pathways: G protein-coupled estrogen receptor (GPER)-dependent activation of the PI3K\/AKT and ERK pathways, which enhanced HIF-1\u03b1 accumulation, and estrogen receptor alpha (ESR1)-mediated transcriptional upregulation of HIF-1\u03b1. These two pathways converged to increase VEGF secretion and ultimately promoted tube formation, migration, and invasion of human umbilical vein endothelial cells. Collectively, these findings demonstrate that under hypoxic conditions, estrogen drives angiogenesis in AM through dual regulation of the HIF-1\u03b1\/VEGF pathway by GPER and ESR1. This study provides new mechanistic insight into the pathogenesis of AM and supports the GPER\/ESR1\u2013HIF-1\u03b1\u2013VEGF axis as a potential mechanistic target for further investigation.<\/jats:p>","DOI":"10.1093\/molehr\/gaag057","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:24:55Z","timestamp":1789755895000},"source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia and estrogen cooperatively enhance angiogenesis through the GPER\/ESR1\u2013HIF-1\u03b1\/VEGF axis in adenomyosis"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2345-8057","authenticated-orcid":false,"given":"Lin","family":"Gan","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine , Nanjing,","place":["China"]},{"name":"Department of Gynecology, Affiliated Jiangning Hospital of Chinese Medicine, China Pharmaceutical University , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Nursing, Nanjing University of Chinese Medicine , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine , Suzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nursing, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9134-8892","authenticated-orcid":false,"given":"Meihua","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4785-6590","authenticated-orcid":false,"given":"Zhenli","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9935-6451","authenticated-orcid":false,"given":"Tao","family":"Gui","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"2026101518563215900_gaag057-B1","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1152\/physrev.00024.2016","article-title":"Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications","volume":"97","author":"Arnal","year":"2017","journal-title":"Physiol 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