Bare-
metal and
drug-eluting stents 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. After
stent implantation,
proteins involved in regulating calcification were upregulated in the
neointima of
drug-eluting stents. 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
drug-eluting stents in comparison with bare-
metal stents. 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 and ADAMTS5 to ADAMTS4 gene 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 cleavage were more abundant in human arteries than in human veins. In addition,
aggrecan synthesis was induced on grafting a vein into the arterial circulation, suggesting an important role for
aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of
aggrecan and a dilation of the thoracic aorta, confirming that
aggrecanase activity regulates
aggrecan abundance in the arterial wall and contributes to
vascular remodeling.
CONCLUSIONS: Significant differences were identified by proteomics in the ECM of coronary arteries after bare-
metal and
drug-eluting stent 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 gene expression. This study provides the first evidence implicating
aggrecan and aggrecanases in the
vascular injury response after stenting.