{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:58:29Z","timestamp":1792706309554,"version":"4.5.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2017,4,28]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Vascular endothelial growth factor (VEGF) is the main driver of angiogenesis and vascular permeability via VEGF receptor 2 (VEGFR2), whereas lymphangiogenesis signals are transduced by VEGFC\/D via VEGFR3. VEGFR3 also regulates sprouting angiogenesis and blood vessel growth, but to what extent VEGFR3 signaling controls blood vessel permeability remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>To investigate the role of VEGFR3 in the regulation of VEGF-induced vascular permeability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Long-term global\n                      <jats:italic>Vegfr3<\/jats:italic>\n                      gene deletion in adult mice resulted in increased fibrinogen deposition in lungs and kidneys, indicating enhanced vascular leakage at the steady state. Short-term deletion of\n                      <jats:italic>Vegfr3<\/jats:italic>\n                      in blood vascular endothelial cells increased baseline leakage in various tissues, as well as in tumors, and exacerbated vascular permeability in response to VEGF, administered via intradermal adenoviral delivery or through systemic injection of recombinant protein.\n                      <jats:italic>VEGFR3<\/jats:italic>\n                      gene silencing upregulated VEGFR2 protein levels and phosphorylation in cultured endothelial cells. Consistent with elevated VEGFR2 activity, vascular endothelial cadherin showed reduced localization at endothelial cell\u2013cell junctions in postnatal retinas after\n                      <jats:italic>Vegfr3<\/jats:italic>\n                      deletion, or after\n                      <jats:italic>VEGFR3<\/jats:italic>\n                      silencing in cultured endothelial cells. Furthermore, concurrent deletion of\n                      <jats:italic>Vegfr2<\/jats:italic>\n                      prevented VEGF-induced excessive vascular leakage in mice lacking\n                      <jats:italic>Vegfr3<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>VEGFR3 limits VEGFR2 expression and VEGF\/VEGFR2 pathway activity in quiescent and angiogenic blood vascular endothelial cells, thereby preventing excessive vascular permeability.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.116.310477","type":"journal-article","created":{"date-parts":[[2017,3,15]],"date-time":"2017-03-15T21:10:35Z","timestamp":1489612235000},"page":"1414-1425","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":157,"title":["VEGFR3 Modulates Vascular Permeability by Controlling VEGF\/VEGFR2 Signaling"],"prefix":"10.1161","volume":"120","author":[{"given":"Krista","family":"Heinolainen","sequence":"first","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinem","family":"Karaman","sequence":"additional","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"D\u2019Amico","sequence":"additional","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas","family":"Tammela","sequence":"additional","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raija","family":"Sormunen","sequence":"additional","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauri","family":"Eklund","sequence":"additional","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Alitalo","sequence":"additional","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Zarkada","sequence":"additional","affiliation":[{"name":"From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D\u2019A., T.T., K.A., G.Z.); Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Finland (R.S.); and Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland (L.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00035.2003"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006502"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.093351"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.054"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2013.08.020"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11017"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.17.4762"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1013"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2545"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5390.946"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07083"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2331"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1423278112"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65583-6"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.99-1049com"},{"key":"e_1_3_5_17_2","first-page":"e50062","article-title":"An in vivo assay to test blood vessel permeability.","author":"Radu M","year":"2013","unstructured":"Radu M, Chernoff J. 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