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To investigate this possibility, we measured real time responses of VEGF, lactate, and HIF-1\u03b1 by retinas and other tissues to rapid and precise decreases in dissolved O\n                    <jats:sub>2.<\/jats:sub>\n                    and showed that retinas, retinal pigment epithelium, and endothelial cells all can secrete VEGF within 5 min after a decrease in [O\n                    <jats:sub>2<\/jats:sub>\n                    ]. HIF-1\u03b1 levels in retinas did not increase until 20 to 30 min after a decrease in dissolved [O\n                    <jats:sub>2<\/jats:sub>\n                    ]. Moreover, increased HIF-1\u03b1 induced by the drug Roxadustat, did not stimulate VEGF secretion at atmospheric (21%) O\n                    <jats:sub>2<\/jats:sub>\n                    and a steady rate of VEGF secretion was sustained for over 120 min following elimination of HIF-1\u03b1 and protein synthesis by exposure to the protein synthesis inhibitor cycloheximide. We then investigated the mechanism of VEGF release and found that VEGF was stored in the plasma membranes of retinas at 21% O\n                    <jats:sub>2<\/jats:sub>\n                    . These stores are depleted within 30 min once [O\n                    <jats:sub>2<\/jats:sub>\n                    ] is decreased. Taken together, these findings indicate that VEGF is constitutively made (under the influence of HIF-1\u03b1 and other transcription factors) and stored within the retina, and rapid release occurs after a substantial decrease in available O\n                    <jats:sub>2<\/jats:sub>\n                    independent of HIF-1\u03b1.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2602872123","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:36:09Z","timestamp":1787675769000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Rapid, HIF-1\u03b1-independent, response of VEGF secretion to decreased O\n                    <sub>2<\/sub>\n                    in mouse 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