Abstract 19387: Extracellular Matrix Remodelling in Porcine Coronary Arteries Upon Stent Implantation

Abstract

Introduction: Extracellular matrix (ECM) remodeling upon vascular stent injury contributes to both neointimal hyperplasia (restenosis) as well as endothelialization (propensity for thrombosis). Despite its important clinical implications little is known about ECM changes post stent implantation. Hypothesis: ECM remodelling, a determinant of stent healing, differs between drug-eluting (DES) and bare-metal stents (BMS). Methods: Using proteomics, we profile changes of vascular ECM proteins over time following implantation of DES and BMS in porcine coronary arteries in an overstretch model. Results: DES (n=14) or BMS (n=14) were implanted in coronary arteries of pigs. Quantitative coronary angiography and optical coherence tomography were performed at 1, 3, 7, 14 and 28 days after stent deployment. Animals were sacrificed at each of these time-points and their coronary arteries were retrieved for subsequent analysis by proteomics. A total of 126 ECM and ECM-associated proteins were identified by mass spectrometry. Within the first week after stent injury, proteins involved in inflammation and thrombosis were elevated in DES and BMS stented arteries. After one week, significant changes in regulatory ECM proteins such as small leucine rich proteins or matricellular proteins were observed. By day 28, differences between BMS and DES became apparent: basement membrane proteins as markers of cellularity were reduced in DES compared with BMS. In contrast, large aggregating proteoglycans such as aggrecan and versican were increased. Both belong to the lectican protein family that act as linkers of ECM molecules with their highly charged glycan side chains. The proteomics findings were validated by immunoblot analysis and real-time polymerase chain reaction. We were also able to detect aggrecan by immunohistochemistry in clinical specimen confirming differential expression patterns of aggrecan and versican in stented human coronary arteries. Conclusions: In the early course after BMS and DES implantation the ECM changes were similar. Significant differences were identified in the regulation of ECM proteins in long-term follow-up consisting of suppression of basement membrane proteins and up-regulation of large aggregating proteoglycans in DES.