{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:15:58Z","timestamp":1787026558505,"version":"build-2736575974"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021711","name":"Bayerisches Staatsministerium f\u00fcr Wissenschaft und Kunst","doi-asserted-by":"publisher","award":["H.4001.1.7-53\/7"],"award-info":[{"award-number":["H.4001.1.7-53\/7"]}],"id":[{"id":"10.13039\/501100021711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Post-COVID-19 syndrome (PCS) is characterized by persistent symptoms such as fatigue, cardiovascular abnormalities, and cognitive impairment. Endothelial dysfunction (ED) has been proposed as a contributing factor, but underlying mechanisms remain unclear. We investigated whether SARS-CoV-2 spike protein subunit 1 (S1) is sufficient to induce ED in human retinal endothelial cells (HRECs)\n                      <jats:italic>in vitro<\/jats:italic>\n                      and whether pharmacologic inhibition of HIF-2\u03b1 signaling modulates endothelial barrier integrity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we characterized 41 PCS patients and 24 pre-pandemic healthy controls. The effects of recombinant S1 and plasma from patients with severe PCS on endothelial function were assessed in HRECs. Belzutifan was used as a pharmacologic probe to assess the role of HIF-2\u03b1 signaling in S1- and plasma-associated endothelial responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PCS patients exhibited elevated erythropoietin, VEGF, and MCP-1 levels compared with controls. VEGF correlated with anti-S1 IgG and was upregulated at the mRNA level in S1-exposed HRECs. Additionally,\n                      <jats:italic>in vitro<\/jats:italic>\n                      exposure to S1 induced ROS production, transient HIF-1\u03b1 and sustained HIF-2\u03b1 activation, VEGFR2 upregulation, and impaired endothelial barrier integrity. Plasma from patients with severe PCS increased ROS production and induced modest alterations in endothelial barrier function in HRECs. In both S1- and PCS-plasma\u2013treated cells, pharmacologic HIF-2\u03b1 inhibition with belzutifan improved endothelial barrier integrity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify a spike-responsive, HIF-2\u03b1\u2013associated ED pathway in retinal endothelial cells. Modulation of this pathway altered endothelial barrier responses to both recombinant S1 and plasma from patients with PCS, highlighting a candidate mechanism that may contribute to PCS-associated vascular dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1770758","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T06:47:24Z","timestamp":1773038844000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["SARS\u2212CoV\u22122 spike S1-mediated HIF\u22122\u03b1 activation in retinal endothelial cells suggests a mechanism contributing to post\u2212COVID endothelial dysfunction"],"prefix":"10.3389","volume":"17","author":[{"given":"Andrea","family":"Ribeiro","sequence":"first","affiliation":[{"name":"School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich","place":["Munich, 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