Abstract
Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE-/- carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.
Highlights
Cardiovascular disease is the most frequent cause of death in industrialized nations
early angiogenic outgrowth cells (EOCs), HUVECs and SMCs were seeded on bare metal nitinol-foils with/ without coating with star-PEG, bio-functionalized with RGD, or RGD in combination with CXCL1
A significant increase in EOC and HUVEC adhesion to RGD but foremost RGD/ CXCL1-biofunctionalized foils was revealed compared to bare-metal controls or star-PEG-coated foils (Fig 1A)
Summary
Cardiovascular disease is the most frequent cause of death in industrialized nations. Atherosclerosis as the underlying disease [1,2] can result in a narrowing of the artery, necessitating angioplasty and stent-implantation. While meta-analyses have shown no differences in stent thrombosis comparing drug-eluting with bare-metal stents [5,6,7], there is evidence of an increased risk of very late stent thrombosis with drug-eluting stents [6,8,9,10], possibly related to reduced vessel wall re-endothelialization [11,12,13]. The chemokine CXCL1 enhances re-endothelialization and reduces neointima formation, and its receptor CXCR2 mediates homing of circulating endothelial progenitor cells to sites of arterial injury in mice [14,15,16]. Stents coated with cRGD (Arg-Gly-Asp)-peptide, which preferentially bind αvβ and α5β-integrins, attract endothelial progenitor cells to stented areas, accelerating wound healing in swine [17]
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