Krista Heinolainen1, Sinem Karaman1, Gabriela D'Amico1, Tuomas Tammela1, Raija Sormunen1, Lauri Eklund1, Kari Alitalo1, Georgia Zarkada2. 1. From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., 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.). 2. From the Wihuri Research Institute and Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland (K.H., S.K., G.D'A., 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.). kari.alitalo@helsinki.fi georgia.zarkada@yale.edu.
Abstract
RATIONALE: 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. OBJECTIVE: To investigate the role of VEGFR3 in the regulation of VEGF-induced vascular permeability. METHODS AND RESULTS: Long-term global Vegfr3 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 Vegfr3 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. VEGFR3 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-cell junctions in postnatal retinas after Vegfr3 deletion, or after VEGFR3 silencing in cultured endothelial cells. Furthermore, concurrent deletion of Vegfr2 prevented VEGF-induced excessive vascular leakage in mice lacking Vegfr3. CONCLUSIONS: VEGFR3 limits VEGFR2 expression and VEGF/VEGFR2 pathway activity in quiescent and angiogenic blood vascular endothelial cells, thereby preventing excessive vascular permeability.
RATIONALE: 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. OBJECTIVE: To investigate the role of VEGFR3 in the regulation of VEGF-induced vascular permeability. METHODS AND RESULTS: Long-term global Vegfr3 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 Vegfr3 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. VEGFR3 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-cell junctions in postnatal retinas after Vegfr3 deletion, or after VEGFR3 silencing in cultured endothelial cells. Furthermore, concurrent deletion of Vegfr2 prevented VEGF-induced excessive vascular leakage in mice lacking Vegfr3. CONCLUSIONS:VEGFR3 limits VEGFR2 expression and VEGF/VEGFR2 pathway activity in quiescent and angiogenic blood vascular endothelial cells, thereby preventing excessive vascular permeability.
Authors: Tatiana V Petrova; Terhi Karpanen; Camilla Norrmén; Russell Mellor; Tomoki Tamakoshi; David Finegold; Robert Ferrell; Dontscho Kerjaschki; Peter Mortimer; Seppo Ylä-Herttuala; Naoyuki Miura; Kari Alitalo Journal: Nat Med Date: 2004-08-22 Impact factor: 53.440
Authors: A Lymboussaki; T A Partanen; B Olofsson; J Thomas-Crusells; C D Fletcher; R M de Waal; A Kaipainen; K Alitalo Journal: Am J Pathol Date: 1998-08 Impact factor: 4.307
Authors: Paula Haiko; Taija Makinen; Salla Keskitalo; Jussi Taipale; Marika J Karkkainen; Megan E Baldwin; Steven A Stacker; Marc G Achen; Kari Alitalo Journal: Mol Cell Biol Date: 2008-06-02 Impact factor: 4.272
Authors: V Joukov; K Pajusola; A Kaipainen; D Chilov; I Lahtinen; E Kukk; O Saksela; N Kalkkinen; K Alitalo Journal: EMBO J Date: 1996-01-15 Impact factor: 11.598
Authors: Tuomas Tammela; Georgia Zarkada; Harri Nurmi; Lars Jakobsson; Krista Heinolainen; Denis Tvorogov; Wei Zheng; Claudio A Franco; Aino Murtomäki; Evelyn Aranda; Naoyuki Miura; Seppo Ylä-Herttuala; Marcus Fruttiger; Taija Mäkinen; Anne Eichmann; Jeffrey W Pollard; Holger Gerhardt; Kari Alitalo Journal: Nat Cell Biol Date: 2011-09-11 Impact factor: 28.824
Authors: Katrien Stouffs; Sari Daelemans; Samuel Santos-Ribeiro; Sara Seneca; Alexander Gheldof; Ali Sami Gürbüz; Michel De Vos; Herman Tournaye; Christophe Blockeel Journal: J Assist Reprod Genet Date: 2018-11-27 Impact factor: 3.412