VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling

摘要

VEGF-A and the VEGF receptors are critical for regulating angiogenesis during development, homeostasis and in pathological conditions, such as cancer and proliferative retinopathies. Most effects of VEGF-A are mediated by the VEGFR2 and its co-receptor, Neuropilin-1 (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 ERK and MAP kinase pathways, thereby also triggering shedding of other ADAM17-substrates, including TNFα, TGFα, HB-EGF, and Tie-2. Interestingly, an ADAM17-selective inhibitor shortens the duration of VEGF-A-stimulated ERK phosphorylation in HUVECs, 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.