Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries

Percutaneous coronary intervention with implantation of stent is the most popular treatment method for coronary artery disease. The implementation of stents led to decreased effect of acute elastic recoil as well as occlusive dissection on restenosis. Unfortunately, stent implantation comes with an excessive healing process, which results in neointimal hyperplasia along with in-stent restenosis in the case of bare-metal stents.

However, in order to mitigate the effects of repeat revascularization and stent restenosis, researchers have found a solution in drug-eluting stents. However, drug-eluting stents implantation has been found to lead to delayed vessel reendothelialization owing to the nonselective nature of the drugs used. This has therefore led to late stent thrombosis, which calls for an extensive dual antiplatelet treatment. It has also been found that late stent thrombosis is a cause of hypersensitivity reactions and inflammation of non-biocompatible polymers coatings used on drug-eluting stents.

Advancement of stent technology has been largely based on using biodegradable polymers and biodegradable nonmetallic scaffolds. Unfortunately, efforts for continuous development of drug-eluting technology have continued to be affected by stent failure caused by in-stent restenosis. The interaction between platelets, smooth muscle cells, endothelial cells, and inflammatory cells constitute neointimal hyperplasia, which results in obliteration of the vascular lumen.

Platelet inflammation and activation increases proliferation, extracellular matrix production, and smooth muscle cells migration. However, there’s an insufficient knowledge about extracellular matrix on vascular stent injury, irrespective of the fact that more than 50% of the neointimal hyperplasia is composed of extracellular matrix proteins.

In an international collaboration, researchers led by Professor Manuel Mayr at King’s British Heart Foundation Centre School of Cardiovascular Medicine & Science in King’s College London ran an extensive proteomics study in order to characterize extracellular matrix remodeling in porcine coronary arteries stented with drug-eluting stents and bare-metal stents. Pigs were selected for the study stemming from the fact that the healing process in pigs nearly resembles the human disease, but neointimal hyperplasia formation is within a shorter period. Their research work is published in peer-reviewed journal, Circulation.

In their experiments, the research team implanted drug-eluting and bare metal stents in pig’s coronary arteries with overstretch. A total of twelve healthy male and female domestic pigs were subjected to the coronary intervention through a transfemoral access. The pigs also received a dose of aspirin and clopidogrel before the coronary intervention in order to prevent the risk of in-stent thrombosis. The researchers then harvested stented segments at different times up to 28 days post-stenting for analyzing proteomics of the neointima and media.

The effects of drug eluting stents surpassed inhibiting the smooth muscle cells proliferation. However, the effects had a larger impact on vascular remodeling by altering extracellular matrix composition. The authors recorded the first changes in the media as being proteins responsible for inflammation as well as thrombosis, which was then followed by changes in the regulatory extracellular matrix proteins. By the end of the 28th day, the authors observed that the basement membrane proteins were reduced in the case of drug-eluting stents as opposed to the bare-metal stents. In addition, the decreased cellularity preceded an increase in production of large aggregating proteoglycans like versican and aggrecan. The results in porcine was confirmed using also human specimens and mice animal models.