VEGF-A Stimulates ADAM17-Dependent Shedding of VEGFR2 and Crosstalk Between VEGFR2 and ERK Signaling

Vascular endothelial growth factor (VEGF)-A and the VEGF receptors are critical for regulating angiogenesis during development and homeostasis and in pathological conditions, such as cancer and proliferative retinopathies. Most effects of VEGF-A are mediated by the VEGFR2 and its coreceptor, neuropi...

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Bibliographic Details
Published in:Circulation research 2008-10, Vol.103 (9), p.916-918
Main Authors: Swendeman, Steven, Mendelson, Karen, Weskamp, Gisela, Horiuchi, Keisuke, Deutsch, Urban, Scherle, Peggy, Hooper, Andrea, Rafii, Shahin, Blobel, Carl P
Format: Article
Language:English
Subjects:
ADAM Proteins - deficiency
ADAM Proteins - genetics
ADAM Proteins - metabolism
ADAM10 Protein
ADAM17 Protein
Amyloid Precursor Protein Secretases - metabolism
Animals
Biological and medical sciences
Chlorocebus aethiops
COS Cells
Endothelial Cells - enzymology
Extracellular Signal-Regulated MAP Kinases - metabolism
Fibroblasts - enzymology
Fundamental and applied biological sciences. Psychology
Humans
Membrane Proteins - metabolism
Mice
Mice, Knockout
Neuropilin-1 - metabolism
Recombinant Fusion Proteins - metabolism
Signal Transduction
Swine
Time Factors
Transfection
Vascular Endothelial Growth Factor A - metabolism
Vascular Endothelial Growth Factor Receptor-2 - genetics
Vascular Endothelial Growth Factor Receptor-2 - metabolism
Vertebrates: cardiovascular system
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Summary:Vascular endothelial growth factor (VEGF)-A and the VEGF receptors are critical for regulating angiogenesis during development and homeostasis and in pathological conditions, such as cancer and proliferative retinopathies. Most effects of VEGF-A are mediated by the VEGFR2 and its coreceptor, neuropilin (NRP)-1. Here, we show that VEGFR2 is shed from cells by the metalloprotease disintegrin ADAM17, whereas NRP-1 is released by ADAM10. VEGF-A enhances VEGFR2 shedding by ADAM17 but not shedding of NRP-1 by ADAM10. VEGF-A activates ADAM17 via the extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase pathways, thereby also triggering shedding of other ADAM17 substrates, including tumor necrosis factor α, transforming growth factor α, heparin-binding epidermal growth factor–like growth factor, and Tie-2. Interestingly, an ADAM17-selective inhibitor shortens the duration of VEGF-A–stimulated ERK phosphorylation in human umbilical vein endothelial cells, providing evidence for an ADAM17-dependent crosstalk between the VEGFR2 and ERK signaling. Targeting the sheddases of VEGFR2 or NRP-1 might offer new opportunities to modulate VEGF-A signaling, an already-established target for treatment of pathological neovascularization.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.108.184416