Importance of alphavbeta3 integrin in arteriogenesis in the peripheral circulation of the rabbit
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The objective of the present study was to investigate the possible role of alphavbeta3 integrin and its main ligand vitronectin in the growth of collateral arteries (arteriogenesis). Integrins are membrane receptor proteins that mediate cell-ECM and cell-to-cell interactions. Among other cells, endothelial cells and smooth muscle cells express alphavbeta3 integrin, and it is implicated in biological processes such as angiogenesis, neointima formation, platelet aggregation and macrophage transmigration. Seventeen male, specific-pathogen-free New Zealand White rabbits with an average weight of 2.5 kg were subjected to experimental occlusion of the femoral artery or sham operated. After 1, 3, 7, 14 or 56 days of femoral occlusion, the vastus intermedius of the quadriceps muscle was excised and cryopreserved. Transversal sections were immunostained with antibodies specific either for alphavbeta3 integrin or vitronectin, and the intensity of immunoperoxidase staining signal was quantified by computer software imaging. The proliferation marker Ki-67 was used to identify growing collateral arteries. Quiescent arteries in sham operated and experimental animals showed alphavbeta3 integrin staining just above the level of detection. A significant increase in integrin content was found in the endothelium of growing collateral arteries 3 days after occlusion (3.2 fold, p<0.005), and in the endothelium and media 7 days after occlusion (3.7 fold, p<0.001; 7 fold, p<0.001; respectively). Fourteen days after occlusion, alphavbeta3 integrin protein already returned to initial levels. The increase was restricted to growing collateral vessels. Contrarily, vitronectin content in the endothelium of growing collaterals 7 days after occlusion decreased compared to controls and returned to initial, higher levels after 14 days. These results demonstrate that alphavbeta3 integrin plays a role in the arteriogenic process but that vitronectin is not the main ligand for alphavbeta3 integrin in arteriogenesis. The functions of this integrin in this context are probably related to macrophage recruitment and/or growth factor receptor clustering, both required for proper collateral development during the proliferative phase. It could also play a role in early vasodilation, in formation of a subsequently remodeled neointima, as a mechanosensor in signal transduction, and as an anti-apoptotic signal. The most probable ligand for alphavbeta3 integrin in the process of arteriogenesis as indicated by previous studies is osteopontin, which is also acting in the vascular system. Considering all the potential functions of alphavbeta3 integrin in arteriogenesis and the different known and possibly unknown ligands of this receptor, it is quite evident that further studies are necessary to elucidate the exact role of alphavbeta3 integrin and to determine its ligand or ligands, if any in the process of arteriogenesis. This is particularly interesting in regard to anti-restenotic therapies, which are prescribed, for example after balloon angioplasty, and include non-specific integrin blockers. This may well interfere with arteriogenesis, which can be regarded as the physiological mechanism for limitation of the consequences of arterial stenosis or occlusion.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen: DVG Service, 2004, http://www.dvg.net/