(D-145) A collagen-binding proangiogenic proteoglycan mimetics promotes rapid endothelializatin and suppresses intimal hyperplasia in a rat angioplasty model

Introduction:: Coronary artery disease (CAD) is the most common type of heart disease and the number one killer of Americans. CAD is a direct result of atherosclerosis, the accumulation of plaque on artery walls and narrowing of arteries’ lumens. Percutaneous coronary intervention (PCI) which mechanically widens the narrowed coronary artery has significantly transformed the care of CAD. However, an inevitable consequence of PCI is damage to the vessel wall at the site of balloon deployment and exposure of the underlying collagenous connective tissue that follows thrombosis, blood clotting, and neointimal hyperplasia, The current project involves the development and evaluation of a novel “paving” technology to improve outcomes following balloon angioplasty for the treatment of atherosclerotic or narrowed arteries. We previously demonstrated that by coupling collagen-binding peptide (SILY) to dermatan sulfate (DS), the damaged vascular wall can be targeted and coated within seconds with an antithrombotic, anti-platelet layer (DS-SILY), and neointimal hyperplasia can be controlled. Recently, using One-Bead One-Compound (OBOC) combinatorial technology, we indetified a novel peptide ligand LXW7, which specifically binds to endothelial cells (ECs) and endothelial progenitor cells (EPCs), and promotes functional endothelialization. In this study, we propose to graft LXW7 to the DS-SILY molecule, will result in a novel, multi-functional molecule (LXW7-DS-SILY) that can be delivered from the end of a catheter following balloon angioplasty to coat the injured vessel area, prevent platelet binding and thrombosis, support capture of EPCs from blood, facilitate reendothelialization, and ultimately reduce neointimal hyperplasia.


Materials and Methods:: The coating efficiency and stability of LXW7-DS-SILY on collagen surface were determined. The effects of the LXW7-DS-SILY on platelet binding and EPC recruitment were evaluated in a flow chamber (in vitro) and on the rat carotid vessel tissue (ex vivo). The effects of the LXW7-DS-SILY on platelet inhibition, EPC recruitment, reendothelialization, and neointimal hyperplasia were further confirmed in a rat carotid artery angioplasty/denudation model.


Results, Conclusions, and Discussions:: Results & Discussion: LXW7-DS-SILY could be coated on the collage surface and collagen-based tissue successfully. The LXW7-SD-SILY coating improved the EPC recruitment and suppressed the platelet adhesion in the flow chamber in vitro and on the rat carotid vessel tissue ex vivo. In vivo, comparing to the untreated group (PBS treated), the DS-SILY coating only suppressed the platelet adhesion, and the LXW7-DS-SILY coating did not only inhibit the platelet adhesion but also promote the EPC recruitment and reendothelialization. The LXW7-DS-SILY further suppressed the neointimal hyperplasia comparing to the untreated group and DS-SILY treated group (Figure 1).

Conclusions: Our innovative approach combining collagen-binding DS-SILY and EPC-binding LXW7 will prevent platelet binding and thrombosis, promote reendothelialization of damaged vessels, and decrease late-lumen loss. This novel therapeutic is expected to substantially reduce the complications associated with the current drug-eluting stents and therefore impact the treatment of patients with cardiovascular disease.


Acknowledgements (Optional): :

References (Optional): :