Abstract P167: CXCR4 Antagonism Is Equally Effective as Sirolimus in Reducing Neointima Formation After Arterial Injury Without Impairing Reendothelialization

Abstract

The chemokine receptor CXCR4 is crucial in neointima formation which is a problem after stent implantation. Drug-eluting stents reduce the restenosis risk but delayed re-endothelialization promotes late stent thrombosis. We compared CXCR4 antagonism with sirolimus treatment in preventing neointima formation after arterial injury in mice. Apolipoprotein E -/- mice after carotid wire injury were given a CXCR4 antagonist (POL5551 (P), a Protein Epitope Mimetic (PEM)) or sirolimus (n=6-8/group). The drugs were administered continuously (P: 2 and 20 mg/kg/d; sirolimus: 1.25 mg/kg/d; osmotic pumps) or intermittently (P: 20 mg/kg; IP, once daily) for 28 days. The neointimal area, smooth muscle cell (SMC) content, macrophage content, and endothelial coverage were quantified by planimetry from injured arteries stained with Elastica van Giesson, or after immunostaining for α-smooth muscle actin, Mac-2, and von Willebrand Factor, respectively. Peripheral Sca-1 + /Lin - smooth muscle progenitor cells (SPCs) were measured by flow cytometry. Treatment with sirolimus as well as with a continuous (C) or intermittent (I), high (H) or low (L) dose (D) of POL5551 (P) reduced the neointimal area compared to corresponding vehicle (Sirolimus: 69%, CHD-P: 70%, CLD-P: 63%, IHD-P: 53%). The relative neointimal content of macrophages increased by sirolimus application (70%). In contrast, the macrophage content decreased by CHD-P and IHD-P application (57% and 37%, respectively). However, CLD-P application did not alter the macrophage content. Sirolimus, CHD-P, and IHD-P highly diminished the neointimal SMC content (78%, 85%, and 67%, respectively), while CLD-P treatment did not. SPC increase in the circulation 1 day post injury was prevented by sirolimus, CHD-P, and IHD-P, but not by CLD-P. The endothelial coverage was not reduced by P, but significantly by sirolimus (14%). In conclusion, CXCR4 antagonism by POL5551 is equally effective as sirolimus in reducing neointima formation after arterial injury in mice. It might be more beneficial than sirolimus because it does not impair re-endothelialization and leads to a more stable lesional phenotype. These results indicate that POL5551 might be a promising alternative for restenosis prevention after stent implantation.