{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:47:24Z","timestamp":1785757644198,"version":"3.56.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diabetic retinopathy (DR) is a leading cause of preventable vision loss worldwide, characterized by retinal microvascular dysfunction and progressive angiogenic dysregulation. Angiopoietin-like protein 2 (ANGPTL2) promotes endothelial activation and pathological angiogenesis in multiple vascular disease contexts, yet its effects on retinal endothelial angiogenic behavior have not been directly characterized. Whether integrin \u03b15\u03b21 and PI3K\/AKT phosphorylation changes in the diabetic retina are associated with alterations in ANGPTL2 expression levels also remains unexamined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ANGPTL2 was overexpressed in human retinal microvascular endothelial cells (HRMECs), and effects on cell viability, wound closure, invasion, and tube formation were assessed by CCK-8, wound healing, Transwell invasion, and tube formation assays. Integrin \u03b15\u03b21, VEGF, and PI3K\/AKT phosphorylation were characterized by western blot. Retinal tissues from streptozotocin (STZ)-induced diabetic rats across groups with varying ANGPTL2 expression levels were analyzed by RT-qPCR, western blot, and immunofluorescence to characterize accompanying molecular changes. The protein-level association between ANGPTL2 and integrin \u03b15\u03b21 was examined by co-immunoprecipitation and co-localization immunofluorescence under overexpression conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ANGPTL2 overexpression significantly enhanced cell viability, wound closure, invasion, and tube formation in HRMECs, accompanied by upregulation of VEGF, p-VEGFR2, integrin \u03b15\u03b21, and PI3K\/AKT phosphorylation. Retinal tissues from STZ-diabetic rats showed elevated integrin \u03b15\u03b21 expression, increased CD31 levels, and increased PI3K\/AKT phosphorylation relative to non-diabetic controls; these molecular changes were directionally lower in the ANGPTL2 knockdown comparison group (i.e., the STZ\u202f+\u202fsh-ANGPTL2 group), providing supportive retinal molecular context. Co-immunoprecipitation and co-localization analyses indicated a protein-level association between ANGPTL2 and integrin \u03b15\u03b21 under overexpression conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ANGPTL2 overexpression promotes angiogenic responses in retinal endothelial cells\n                      <jats:italic>in vitro<\/jats:italic>\n                      , with accompanying integrin \u03b15\u03b21 upregulation and broader signaling-associated phosphorylation changes. Retinal tissue molecular findings and the ANGPTL2\u2013integrin \u03b15\u03b21 protein-level association provide supportive molecular context. The functional roles of specific molecular partners in mediating these responses remain to be determined through targeted validation studies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1846631","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:10:15Z","timestamp":1785755415000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ANGPTL2 overexpression promotes angiogenic responses in human retinal microvascular endothelial cells with accompanying integrin \u03b15\u03b21 molecular changes"],"prefix":"10.3389","volume":"13","author":[{"given":"Jiajia","family":"Song","sequence":"first","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University","place":["Hefei, China"]},{"name":"The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofang","family":"Han","sequence":"additional","affiliation":[{"name":"The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Chen","sequence":"additional","affiliation":[{"name":"The Second People\u2019s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianrong","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University","place":["Hefei, 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