{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T23:06:22Z","timestamp":1780095982779,"version":"3.54.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011798","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T00:00:00Z","timestamp":1708387200000}}],"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"crossref","award":["R01-GM129074"],"award-info":[{"award-number":["R01-GM129074"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01-HL101200"],"award-info":[{"award-number":["R01-HL101200"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The vascular endothelial growth factor (VEGF) family of cytokines are key drivers of blood vessel growth and remodeling. These ligands act via multiple VEGF receptors (VEGFR) and co-receptors such as Neuropilin (NRP) expressed on endothelial cells. These membrane-associated receptors are not solely expressed on the cell surface, they move between the surface and intracellular locations, where they can function differently. The location of the receptor alters its ability to \u2019see\u2019 (access and bind to) its ligands, which regulates receptor activation; location also alters receptor exposure to subcellularly localized phosphatases, which regulates its deactivation. Thus, receptors in different subcellular locations initiate different signaling, both in terms of quantity and quality. Similarly, the local levels of co-expression of other receptors alters competition for ligands. Subcellular localization is controlled by intracellular trafficking processes, which thus control VEGFR activity; therefore, to understand VEGFR activity, we must understand receptor trafficking. Here, for the first time, we simultaneously quantify the trafficking of VEGFR1, VEGFR2, and NRP1 on the same cells\u2014specifically human umbilical vein endothelial cells (HUVECs). We build a computational model describing the expression, interaction, and trafficking of these receptors, and use it to simulate cell culture experiments. We use new quantitative experimental data to parameterize the model, which then provides mechanistic insight into the trafficking and localization of this receptor network. We show that VEGFR2 and NRP1 trafficking is not the same on HUVECs as on non-human ECs; and we show that VEGFR1 trafficking is not the same as VEGFR2 trafficking, but rather is faster in both internalization and recycling. As a consequence, the VEGF receptors are not evenly distributed between the cell surface and intracellular locations, with a very low percentage of VEGFR1 being on the cell surface, and high levels of NRP1 on the cell surface. Our findings have implications both for the sensing of extracellular ligands and for the composition of signaling complexes at the cell surface versus inside the cell.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011798","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T13:39:45Z","timestamp":1707313185000},"page":"e1011798","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Trafficking dynamics of VEGFR1, VEGFR2, and NRP1 in human endothelial cells"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5097-5509","authenticated-orcid":true,"given":"Sarvenaz","family":"Sarabipour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-220X","authenticated-orcid":true,"given":"Karina","family":"Kinghorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn M.","family":"Quigley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Kovacs-Kasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian H.","family":"Annex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria L.","family":"Bautch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3481-7740","authenticated-orcid":true,"given":"Feilim","family":"Mac Gabhann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"pcbi.1011798.ref001","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nrcardio.2013.70","article-title":"Therapeutic angiogenesis for critical limb ischaemia","volume":"10","author":"BH Annex","year":"2013","journal-title":"Nat Rev Cardiol"},{"key":"pcbi.1011798.ref002","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1161\/CIRCRESAHA.121.318266","article-title":"New directions in therapeutic angiogenesis and arteriogenesis in peripheral arterial disease","volume":"128","author":"BH Annex","year":"2021","journal-title":"Circ 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