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Proteomics Comparison of Extracellular Matrix Remodelling in Porcine Coronary Arteries upon Stent Implantation

Student thesis: Doctoral ThesisDoctor of Philosophy

BACKGROUND Extracellular matrix (ECM) remodelling related to arterial injury and healing after stenting contributes to both, in-stent restenosis and thrombosis. Despite its important clinical implications little is known about ECM changes post-stent implantation.

METHODS Bare-metal (BMS) and drug-eluting stents (DES) were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14 and 28 days post-stenting for proteomics analysis of the media and neointima.

RESULTS A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. The composition of the neointimal ECM was more diverse than of the media, and proteins involved in regulating calcification were upregulated in the neointima of DES. After stent implantation the earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in DES compared with BMS. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 to ADAMTS4 expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan fragments were more abundant in human arteries compared to veins. Also, aggrecan synthesis was induced upon grafting a vein into the arterial circulation, indicating an important role for aggrecan in vascular plasticity.

CONCLUSIONS Significant differences were identified by proteomics in the ECM of coronary arteries after BMS and DES implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting.
Original languageEnglish
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Award date2017

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