A disintegrin and metalloprotease 10 is a novel mediator of vascular endothelial growth factor-induced endothelial cell function in angiogenesis and is associated with atherosclerosis.
OBJECTIVE
To elucidate the downstream mechanisms of vascular endothelial growth factor receptor 2 (VEGFR2), a key receptor in angiogenesis, which has been associated with atherosclerotic plaque growth and instability.


RESULTS
By using a yeast-2-hybrid assay, we identified A Disintegrin And Metalloprotease 10 (ADAM10) as a novel binding partner of VEGFR2. ADAM10 is a metalloprotease with sheddase activity involved in cell migration; however, its exact function in endothelial cells (ECs), angiogenesis, and atherosclerosis is largely unknown. For the first time to our knowledge, we show ADAM10 expression in human atherosclerotic lesions, associated with plaque progression and neovascularization. We demonstrate ADAM10 expression and activity in ECs to be induced by VEGF; also, ADAM10 mediates the ectodomain shedding of VEGFR2. Furthermore, VEGF induces ADAM10-mediated cleavage of vascular endothelium (VE)-cadherin, which could increase vascular permeability and facilitate EC migration. Indeed, VEGF increases vascular permeability in an ADAM10- and ADAM17-dependent way; inhibition of ADAM10 reduces EC migration and chemotaxis.


CONCLUSIONS
These data provide the first evidence of ADAM10 expression in atherosclerosis and neovascularization. ADAM10 plays a functional role in VEGF-induced EC function. These data open perspectives for novel therapeutic interventions in vascular diseases.
Donners
Marjo M P C
MM
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, 6200 Maastricht, the Netherlands. marjo.donners@gen.unimaas.nl
Wolfs
Ine M J
IM
Olieslagers
Servé
S
Mohammadi-Motahhari
Zeynab
Z
Tchaikovski
Vadim
V
Heeneman
Sylvia
S
van Buul
Jaap D
JD
Caolo
Vincenza
V
Molin
Daniël G M
DG
Post
Mark J
MJ
Waltenberger
Johannes
J
D051722:ADAM Proteins / Q000096:biosynthesis / Q000502:physiology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D018450:Disease Progression; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000503:physiopathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
D008565:Membrane Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human