{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:50:32Z","timestamp":1791366632654,"version":"4.3.1"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Transcriptional regulation is fundamental to vascular homeostasis, ensuring vessel stability and function. Disruption of this regulation underlies pathological angiogenesis in cancer and vascular malformations. While RUNX3 (Runt-related transcription factor 3), a Runt-domain transcription factor, is established as a tumor suppressor and regulator of lymphocyte development, its role in endothelial cells has remained unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>To define the vascular function of RUNX3, we generated endothelial-specific RUNX3 knockout mice and analyzed postnatal retinal angiogenesis and oxygen-induced retinopathy. Mechanistic insights were obtained through ATAC-sequencing data analysis, coimmunoprecipitation, proximity ligation assay, electrophoretic mobility shift assay, and ChIP-qPCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Loss of endothelial RUNX3 induced hypersprouting angiogenesis with excessive tip cell formation and reduced DLL4 (delta-like ligand 4) expression. RUNX3 deficiency disrupted vascular integrity by lowering VE-cadherin (vascular endothelial cadherin) and claudin-5 levels, while increasing ICAM1 (intercellular adhesion molecule 1) expression, retinal hemorrhage, and leukocyte infiltration. In the oxygen-induced retinopathy model, endothelial RUNX3 deletion aggravated pathological neovascularization. Mechanistically, RUNX3 cooperated with ERG (ETS-related gene) at ETS:RUNX motifs to regulate genes controlling sprouting (\n                      <jats:italic toggle=\"yes\">DLL4<\/jats:italic>\n                      ), junctional stability (\n                      <jats:italic toggle=\"yes\">CDH5<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">CLDN5<\/jats:italic>\n                      ), and leukocyte adhesion (\n                      <jats:italic toggle=\"yes\">ICAM1<\/jats:italic>\n                      ). RUNX3 formed complexes with ERG, p300, and HDAC3 (histone deacetylase 3), and proximity ligation assays showed that these interactions were enriched in the nucleus upon VEGF-A (vascular endothelial growth factor-A) stimulation. ChIP-qPCR further demonstrated that RUNX3 was required for the recruitment of these coregulators to target loci. Through differential coregulator engagement, RUNX3 functioned bidirectionally, acting as a transcriptional activator of\n                      <jats:italic toggle=\"yes\">CDH5<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">CLDN5<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">DLL4<\/jats:italic>\n                      while serving as a repressor of\n                      <jats:italic toggle=\"yes\">ICAM1<\/jats:italic>\n                      . Consistently, single-cell transcriptome analysis of human arteriovenous malformations revealed dysregulated RUNX3 and target gene expression, underscoring translational relevance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This study provides the first evidence that RUNX3 is a pivotal transcriptional coordinator in endothelial cells. By integrating ERG and chromatin regulators at ETS:RUNX motifs, RUNX3 safeguards the balance between angiogenic activation and vascular stability. These findings establish RUNX3 as a gatekeeper of endothelial transcriptional identity and highlight its potential as a therapeutic target in pathological angiogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327641","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T09:00:16Z","timestamp":1791363616000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["RUNX3-ERG Cooperation Orchestrates Endothelial Gene Regulation and Vascular Homeostasis"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7999-4119","authenticated-orcid":true,"given":"Jihye","family":"You","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Pathophysiology (J.Y., M.K., S.H.B., L.K., J.M., S.H., Y.M.L.), College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC) (J.Y., M.K., S.H.B., L.K., J.M., S.H., J.-H.J., Y.M.L.), College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea."},{"name":"BK21 Four-Based Intelligent Novel Drug Discovery Education Unit (J.Y., M.K., L.K., J.M., S.H., Y.M.L.), College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhyuk","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathophysiology (J.Y., M.K., S.H.B., L.K., J.M., S.H., Y.M.L.), College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Vessel-Organ Interaction Research Center, VOICE (MRC) (J.Y., M.K., S.H.B., L.K., J.M., S.H., J.-H.J., Y.M.L.), College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea."},{"name":"BK21 Four-Based Intelligent Novel Drug Discovery Education Unit (J.Y., M.K., L.K., J.M., S.H., Y.M.L.), College of Pharmacy, Kyungpook National University, 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