{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:15:55Z","timestamp":1791854155555,"version":"4.3.4"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008695","name":"Japan Foundation for Applied Enzymology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008667","name":"SENSHIN Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008667","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["23gk0210037h0001"],"award-info":[{"award-number":["23gk0210037h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JSPS Overseas Research Fellowship 2022"},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["JP18K08096"],"award-info":[{"award-number":["JP18K08096"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["JP19K17551"],"award-info":[{"award-number":["JP19K17551"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["JP22K16064"],"award-info":[{"award-number":["JP22K16064"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013642","name":"Japan Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013642","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","award":["DK 062729"],"award-info":[{"award-number":["DK 062729"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AHA Northeast Research Consortium Postdoctoral Fellowship"},{"name":"Uehara Research Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Oestrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Oestrogen receptor \u03b1 (ER\u03b1) non-nuclear signalling confers protection against heart failure remodelling, involving myocardial cyclic guanosine monophosphate (cGMP)\u2013cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examine the cell type\u2013specific role of ER\u03b1 non-nuclear signalling in oestrogen-conferred protection against heart failure.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We first assessed the tissue-specific impacts of ER\u03b1 on the cardiac benefits derived from oestrogen, utilizing endothelial ER\u03b1 deletion (ER\u03b1f\/f\/Tie2Cre+) and myocyte ER\u03b1 deletion (ER\u03b1f\/f\/\u03b1MHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3 weeks of pressure overload [transverse aortic constriction (TAC)]. E2 failed to improve cardiac function in ER\u03b1f\/f\/Tie2Cre+ TAC hearts but provided benefits in ER\u03b1f\/f\/\u03b1MHCCre+ TAC hearts, indicating that endothelial ER\u03b1 is essential. We next assessed the role of non-nuclear signalling in endothelial cells (ECs), employing animals with endothelial-specific inactivation of ER\u03b1 non-nuclear signalling (ER\u03b1KI\/KI\/Tie2Cre+). Female ovariectomized mice were supplemented with E2 and subjected to 3-week TAC. ER\u03b1KI\/KI\/Tie2Cre+TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which were associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed by CD31-stained capillary density. This phenotype of ER\u03b1KI\/KI\/Tie2Cre+was rescued by myocardial PKG activation from chronic treatment with a soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial\u2013cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required a co-existence of intact endothelial ER\u03b1 signalling in a nitric oxide synthase-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of ECs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>An endothelial oestrogen\u2013myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure overload.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvae202","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T12:53:57Z","timestamp":1725972837000},"page":"1884-1897","source":"Crossref","is-referenced-by-count":21,"title":["Endothelial oestrogen\u2013myocardial cyclic guanosine monophosphate axis critically determines angiogenesis and cardiac performance during pressure overload"],"prefix":"10.1093","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5994-0668","authenticated-orcid":false,"given":"Nobuaki","family":"Fukuma","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]},{"name":"Division of Cardiology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons , New York, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Tokiwa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]},{"name":"Department of Computational Diagnostic Radiology and Preventive Medicine, The University of Tokyo Hospital , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genri","family":"Numata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]},{"name":"Isotope Science Center, The University of Tokyo , Tokyo 113-0032 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0509-1840","authenticated-orcid":false,"given":"Kazutaka","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3318-9757","authenticated-orcid":false,"given":"Pang-Yen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyu","family":"Tajima","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Otsu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Kariya","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]},{"name":"Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Hiroi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, National Center for Global Health and Medicine , Tokyo ,","place":["Japan"]},{"name":"Vascular Medicine Research, Brigham and Women\u2019s Hospital, Harvard Medical School , Cambridge, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K","family":"Liao","sequence":"additional","affiliation":[{"name":"Vascular Medicine Research, Brigham and Women\u2019s Hospital, Harvard Medical School , Cambridge, MA ,","place":["USA"]},{"name":"Department of Medicine, University of Arizona , Tucson, AZ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0714-7182","authenticated-orcid":false,"given":"Issei","family":"Komuro","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7767-0094","authenticated-orcid":false,"given":"Eiki","family":"Takimoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1, Hongo, Bunkyo, Tokyo 113-8655 ,","place":["Japan"]},{"name":"Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions , 720 Rutland Avenue, Baltimore, MD 21205 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"2024121018221097200_cvae202-B1","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1093\/cvr\/cvac013","article-title":"Global burden of heart failure: a comprehensive and updated review of epidemiology","volume":"118","author":"Savarese","year":"2023","journal-title":"Cardiovasc Res"},{"key":"2024121018221097200_cvae202-B2","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1016\/j.jacc.2022.02.013","article-title":"Sex-based differences in heart failure: JACC Focus Seminar 7\/7","volume":"79","author":"Khan","year":"2022","journal-title":"J Am Coll Cardiol"},{"key":"2024121018221097200_cvae202-B3","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0735-1097(01)01700-4","article-title":". 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