The role of ADAM-mediated shedding in vascular biology

被引:178
作者
Dreymueller, Daniela
Pruessmeyer, Jessica
Groth, Ester
Ludwig, Andreas [1 ]
机构
[1] Rhein Westfal TH Aachen, Inst Pharmacol & Toxicol, D-52074 Aachen, Germany
关键词
Metalloproteinase; Shedding; Vasculature; Signalling; Inflammation; NECROSIS-FACTOR-ALPHA; METALLOPROTEASE-DISINTEGRIN ADAM8; EPIDERMAL-GROWTH-FACTOR; CONVERTING-ENZYME TACE; HUMAN ATHEROSCLEROTIC PLAQUES; TRANSMEMBRANE CXC-CHEMOKINE; ADHESION MOLECULE-1 VCAM-1; MELTRIN-BETA ADAM19; TNF-ALPHA; L-SELECTIN;
D O I
10.1016/j.ejcb.2011.09.003
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Within the vasculature the disintegrins and metalloproteinases (ADAMs) 8, 9, 10, 12, 15, 17, 19, 28 and 33 are expressed on endothelial cells, smooth muscle cells and on leukocytes. As surface-expressed proteases they mediate cleavage of vascular surface molecules at an extracellular site close to the membrane. This process is termed shedding and leads to the release of a soluble substrate ectodomain thereby critically modulating the biological function of the substrate. In the vasculature several surface molecules undergo ADAM-mediated shedding including tumour necrosis factor (TNF) alpha, interleukin (IL) 6 receptor alpha, L-selectin, vascular endothelial (VE)-cadherin, the transmembrane CX3C-chemokine ligand (CX3CL) 1, Notch, transforming growth factor (TGF) and heparin-binding epidermal growth factor (HB-EGF). These substrates play distinct roles in vascular biology by promoting inflammation, permeability changes, leukocyte recruitment, resolution of inflammation, regeneration and/or neovascularisation. Especially ADAM17 and ADAM10 are capable of cleaving many substrates with diverse function within the vasculature, whereas other ADAMs have a more restricted substrate range. Therefore, targeting ADAM17 or ADAM10 by pharmacologic inhibition or gene knockout not only attenuates the inflammatory response in animal models but also affects tissue regeneration and neovascularisation. Recent discoveries indicate that other ADAMs (e.g. ADAM8 and 9) also play important roles in vascular biology but appear to have more selective effects on vascular responses (e.g. on neovascularisation only). Although, targeting of ADAM17 and ADAM10 in inflammatory diseases is still a promising approach, temporal and spatial as well as substrate-specific inhibition approaches are required to minimise undesired side effects on vascular cells. (C) 2011 Elsevier GmbH. All rights reserved.
引用
收藏
页码:472 / 485
页数:14
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