{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:05:33Z","timestamp":1790874333357,"version":"4.1.0"},"reference-count":63,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2007,2,20]],"date-time":"2007-02-20T00:00:00Z","timestamp":1171929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2007,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vascular endothelial growth factor (VEGF), a potent mediator of endothelial proliferation and migration, has an important role also in brain edema formation during hypoxia and ischemia. VEGF binds to the tyrosine kinase receptors Flt\u20101 and Flk\u20101. Yet, their relative importance for hypoxia\u2010induced hyperpermeability is not well understood. We used an in vitro blood\u2010brain barrier (BBB) model consisting of porcine brain microvascular endothelial cells (BMEC) to determine the role of Flt\u20101 in VEGF\u2010induced endothelial cell (EC) barrier dysfunction. Soluble Flt\u20101 abolished hypoxia\/VEGF\u2010induced hyperpermeability. Furthermore, selective antisense oligonucleotides to Flt\u20101, but not to Flk\u20101, inhibited hypoxia\u2010induced permeability changes. Consistent with these data, addition of the receptor\u2010specific homolog placenta\u2010derived growth factor, which binds Flt\u20101 but not Flk\u20101, increased endothelial permeability to the same extent as VEGF, whereas adding VEGF\u2010E, a viral VEGF molecule from the orf virus family activating Flk\u20101 and neuropilin\u20101, but not Flt\u20101, did not show any effect. Using the carcinoma submandibular gland cell line (CSG), only expressing Flt\u20101, it was demonstrated that activation of Flt\u20101 is sufficient to induce hyperpermeability by hypoxia and VEGF. Hyperpermeability, induced by hypoxia\/VEGF, depends on activation of phosphatidylinositol 3\u2010kinase\/Akt (PI3\u2010K\/Akt), nitric oxide synthase (NOS) and protein kinase G (PKG). The activation of the PI3\u2010K\/Akt pathway by hypoxia was confirmed using an in vivo mice hypoxia model. These results demonstrate that hypoxia\/VEGF\u2010induced hyperpermeability can be mediated by activation of Flt\u20101 independently on the presence of Flk\u20101 and indicate a central role for activation of the PI3\u2010K\/Akt pathway, followed by induction of NOS and PKG activity. J. Cell. Physiol. 212: 236\u2013243, 2007. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.21022","type":"journal-article","created":{"date-parts":[[2007,2,20]],"date-time":"2007-02-20T19:42:15Z","timestamp":1172000535000},"page":"236-243","source":"Crossref","is-referenced-by-count":62,"title":["Flt\u20101, but not Flk\u20101 mediates hyperpermeability through activation of the PI3\u2010K\/Akt pathway"],"prefix":"10.1002","volume":"212","author":[{"given":"Carsten","family":"Vogel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Wiesnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus 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