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

• DOI: 10.1161/circresaha.108.184416
• Publication Date: 2008-09-26T01:09:19Z
• Authors: Steven Swendeman; Karen Mendelson; Gisela Weskamp; Keisuke Horiuchi; Urban Deutsch; Peggy Scherle; Andrea Hooper; Shahin Rafii; Carl P. Blobel
• Keywords: Mice, Knockout; 0303 health sciences; Time Factors; Swine; Recombinant Fusion Proteins; Endothelial Cells; Membrane Proteins; ADAM17 Protein; Fibroblasts; Transfection; Neuropilin-1; 3. Good health; ADAM Proteins; ADAM10 Protein; Mice; 03 medical and health sciences; COS Cells; Chlorocebus aethiops; Animals; Humans; Amyloid Precursor Protein Secretases; Extracellular Signal-Regulated MAP Kinases; Signal Transduction

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.