Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice

PLoS One. 2016 May 18;11(5):e0155829. doi: 10.1371/journal.pone.0155829. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alloys / chemistry
  • Animals
  • Carotid Stenosis / etiology
  • Carotid Stenosis / prevention & control*
  • Cell Adhesion / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemokine CXCL1 / chemistry
  • Chemokine CXCL1 / pharmacology*
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology
  • Mice
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Stents / adverse effects*

Substances

  • Alloys
  • Chemokine CXCL1
  • Oligopeptides
  • nitinol
  • arginyl-glycyl-aspartic acid

Grants and funding

This project was funded by the Deutsche Forschungsgemeinschaft (GRK 1035, ZE 827/4-1), the European Research Council Advanced Grant 249929 “Atheroprotect”, the Deutsches Zentrum für Herz-Kreislaufforschung (MHA VD1.2), the European Regional Development Fund and the state of North Rhine-Westphalia, Germany, under the Operational Program "Regional Competitiveness and Employment" 2007–2013 and the Interdisciplinary Centre for Clinical Research IZKF Aachen (junior research group to E.A.L.) within the faculty of Medicine at RWTH Aachen University.