title: VEGF-A induces its negative regulator, soluble form of VEGFR-1, by modulating its alternative splicing.
abstract: Vascular endothelial growth factor-A (VEGF-A) is one of the major angiogenic factors, and its actions are primarily mediated through its two membrane receptors, VEGFR-1 and VEGFR-2. A soluble form of VEGFR-1 (sVEGFR-1) sequesters the free form of VEGF-A, and acts as a potent anti-angiogenic factor. While sVEGFR-1 is synthesized as a splice variant of VEGF-R1 gene, the interactions between VEGF-A and sVEGFR-1 remain largely unknown. Here, we show that VEGF-A upregulates sVEGF-R1 expression in human vascular endothelial cells but leaves full-length VEGF-R1 expression unchanged, and that this induction was dependent on the VEGFR-2-protein kinase C-MEK signaling pathway. The VEGF-A-induced sVEGFR-1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Saito
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.forename: Eisuke
authors.initials: E
authors.lastname: Amiya
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nakao
authors.forename: Hajime
authors.initials: H
authors.lastname: Abe
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Semba
authors.forename: Katsura
authors.initials: K
authors.lastname: Soma
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Koyama
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hosoya
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Imai
authors.forename: Takayuki
authors.initials: T
authors.lastname: Isagawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Koji
authors.initials: K
authors.lastname: Maemura
mesh_terms: D017398:Alternative Splicing; D002478:Cells, Cultured; D025461:Feedback, Physiological; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007438:Introns; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases