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Understanding the vein-to-artery (v2a) transition could improve revascularization therapies, but progress is limited by a lack of human models. Here, we develop a human pluripotent stem cell differentiation protocol that models the v2a EC conversion. Comparing v2a and mesoderm-to-artery transcriptomes with publicly available single-cell RNA sequencing data from human embryos showed they reflected angiogenesis- and vasculogenesis-derived artery ECs, respectively. This reductionist system revealed that VEGF activation alongside PI3K inhibition was sufficient for vein ECs to acquire arterial identity within 48\u2005h. In summary, we model a critical step in vascular development and define the minimal signals required for artery differentiation from veins, providing a framework to promote this conversion in revascularization or therapeutic contexts.<\/jats:p>","DOI":"10.1242\/dev.205490","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T07:32:37Z","timestamp":1781508757000},"source":"Crossref","is-referenced-by-count":1,"title":["Human vein-to-artery endothelial cell fate transition is driven by VEGF\/ERK activation and PI3K inhibition"],"prefix":"10.1242","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1429-1729","authenticated-orcid":false,"given":"Zhainib A.","family":"Amir-Ugokwe","sequence":"first","affiliation":[{"name":"Stanford University 1 Department of Biology , , Stanford, CA 94305,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alanna L.","family":"Pyke","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine 2 Department of Genetics , , Stanford, CA 94305,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8610-3075","authenticated-orcid":false,"given":"Emily","family":"Trimm","sequence":"additional","affiliation":[{"name":"Stanford University 1 Department of Biology , , Stanford, CA 94305,","place":["USA"]},{"name":"Stanford University School of Medicine 3 Biophysics Graduate Program , , Stanford, CA 94305,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7681-5634","authenticated-orcid":false,"given":"Meenakshi","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine 2 Department of Genetics , , Stanford, CA 94305,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3334-7122","authenticated-orcid":false,"given":"Xiaochen","family":"Fan","sequence":"additional","affiliation":[{"name":"Stanford University 1 Department of Biology , , Stanford, CA 94305,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6783-4662","authenticated-orcid":false,"given":"Lay Teng","family":"Ang","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine 4 , Stanford, CA 94305,","place":["USA"]},{"name":"Stanford University School of Medicine 5 Department of Urology , , Stanford, CA 94305,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8042-0149","authenticated-orcid":false,"given":"Kyle M.","family":"Loh","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine 4 , Stanford, CA 94305,","place":["USA"]},{"name":"Stanford University School of Medicine 6 Department of Developmental Biology , , Stanford, CA 94305,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1541-601X","authenticated-orcid":false,"given":"Kristy","family":"Red-Horse","sequence":"additional","affiliation":[{"name":"Stanford University 1 Department of Biology , , Stanford, CA 94305,","place":["USA"]},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine 4 , Stanford, CA 94305,","place":["USA"]},{"name":"Howard Hughes Medical Institute 7 , Chevy Chase , MD 20815 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