{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:40:19Z","timestamp":1792608019722,"version":"4.5.0"},"reference-count":84,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Right ventricular (RV) adaptation to increased afterload determines survival in pulmonary hypertension (PH) and is sexually dimorphic and more preserved in females, mediated in part by protective ER\u03b1 (estrogen receptor \u03b1) signaling in cardiomyocytes. However, effects of ER\u03b1 on RV endothelial cells (RVECs), a critical mediator of RV adaptation, are unknown. We hypothesized that ER\u03b1 exerts sexually dimorphic proangiogenic effects on RVECs in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We isolated RVECs from male and female rats with an ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      (ER\u03b1 loss-of-function mutation) or wild-type controls and assessed angiogenesis end points. Male and female ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      or wild-type rats were treated with monocrotaline or underwent pulmonary arterial banding. Single-nucleus RNA sequencing was performed to investigate RVEC transcriptomic changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Compared with cells isolated from wild-type animals, RVECs from male and female ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      rats exhibited reduced ability to form pseudovascular networks, sprout, and migrate. RVECs from female ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      rats demonstrated increased apoptosis. Restoring migration rescued the impaired angiogenic phenotype in female ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      RVECs. Female monocrotaline-PH ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      rats exhibited increased RV hypertrophy and reduced RV capillary density before (10 days) and at the time of established PH (28 days). Female ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      pulmonary arterial banding rats also exhibited decreased RV capillary density. Capillary rarefaction was associated with decreased tip cell abundance and increased RVEC apoptosis, and a net loss of the endocardial RVEC subpopulation. Differentially expressed gene analysis and pathway analysis identified decreased expression of migration pathways and increased expression of apoptosis pathways in capillary and endocardial RVECs from female but not male monocrotaline-PH ER\u03b1\n                      <jats:sup>Mut<\/jats:sup>\n                      rats.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>ER\u03b1 exhibits a sex-specific endothelial-intrinsic role that is essential for RV angiogenesis under both homeostatic and pathological conditions. This effect appears to stem from enhanced survival and migration capacity of capillary and endocardial RVECs. ER\u03b1 may be a potential target for sex-specific RV-directed therapies in PH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.325390","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:00:20Z","timestamp":1789030820000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Sexually Dimorphic Role of Estrogen Receptor \u03b1 in Preserving Right Ventricular Endothelial Integrity"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2661-0950","authenticated-orcid":true,"given":"Jiajun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Molecular Medicine (J.L.), University of Colorado, Anschutz Medical Campus, Aurora."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijaya","family":"Karoor","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and 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Z.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4291-1788","authenticated-orcid":true,"given":"Chen-Shan Chen","family":"Woodcock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-2600","authenticated-orcid":true,"given":"Irina","family":"Petrache","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine (V.K., I.P., T.L.), University of Colorado, Anschutz Medical Campus, Aurora."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-7923","authenticated-orcid":true,"given":"Zhiyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Critical Care and Medicine, Department of Medicine, Washington University School of Medicine in St. Louis, MO (H.Z., S.L., 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