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VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling

Circulation research, 2017-04, Vol.120 (9), p.1414-1425 [Peer Reviewed Journal]

2017 American Heart Association, Inc. ;Copyright Lippincott Williams & Wilkins Ovid Technologies Apr 28, 2017 ;ISSN: 0009-7330 ;EISSN: 1524-4571 ;DOI: 10.1161/CIRCRESAHA.116.310477 ;PMID: 28298294

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Title:
VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling
Author: Heinolainen, Krista ; Karaman, Sinem ; D’Amico, Gabriela ; Tammela, Tuomas ; Sormunen, Raija ; Eklund, Lauri ; Alitalo, Kari ; Zarkada, Georgia
Subjects: Adherens Junctions - metabolism ; Angiogenesis ; Animals ; Antigens, CD - metabolism ; Cadherin ; Cadherins - metabolism ; Capillary Permeability - drug effects ; Carcinoma, Lewis Lung - blood supply ; Carcinoma, Lewis Lung - metabolism ; Cell junctions ; Cells, Cultured ; Clonal deletion ; Endothelial cells ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Female ; Fibrinogen ; Gene deletion ; Gene silencing ; Genotype ; Human Umbilical Vein Endothelial Cells - metabolism ; Humans ; Kidneys ; Leakage ; Localization ; Lung - blood supply ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Muridae ; Neovascularization, Pathologic ; Neovascularization, Physiologic ; Permeability ; Phenotype ; Phosphorylation ; Retinal Vessels - drug effects ; Retinal Vessels - metabolism ; Rodents ; Signal Transduction - drug effects ; Tight Junctions - metabolism ; Transfection ; Tumors ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor A - pharmacology ; Vascular Endothelial Growth Factor Receptor-2 - deficiency ; Vascular Endothelial Growth Factor Receptor-2 - genetics ; Vascular Endothelial Growth Factor Receptor-2 - metabolism ; Vascular Endothelial Growth Factor Receptor-3 - deficiency ; Vascular Endothelial Growth Factor Receptor-3 - genetics ; Vascular Endothelial Growth Factor Receptor-3 - metabolism ; Vascular endothelial growth factor receptors
Is Part Of: Circulation research, 2017-04, Vol.120 (9), p.1414-1425
Description: 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.
Publisher: United States: American Heart Association, Inc
Language: English
Identifier: ISSN: 0009-7330
EISSN: 1524-4571
DOI: 10.1161/CIRCRESAHA.116.310477
PMID: 28298294
Source: Geneva Foundation Free Medical Journals at publisher websites
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VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling

2017 American Heart Association, Inc. ;Copyright Lippincott Williams & Wilkins Ovid Technologies Apr 28, 2017 ;ISSN: 0009-7330 ;EISSN: 1524-4571 ;DOI: 10.1161/CIRCRESAHA.116.310477 ;PMID: 28298294

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