Impaired endothelial recovery after the implantation of
drug-eluting stents is a major concern because of the increased risk for late
stent thrombosis. The disruption of the
chemokine axis CXCL12/CXCR4 inhibits
neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for
stent coating, we studied the effects of the CXCR4 antagonist
POL5551 and the
drug sirolimus on
neointima formation.
Apolipoprotein E-deficient mice were treated with
POL5551 or
sirolimus continuously for 28 days after a carotid wire injury.
POL5551 inhibited
neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison,
sirolimus reduced the neointimal area by 69%. In contrast to treatment with
POL5551 during the first three days after injury, injection of
POL5551 (20 mg/kg) once per day for 28 days diminished neointimal
hyperplasia by 53%. An analysis of the cellular composition of the
neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of
POL5551. In contrast, the diminished SMC content after
sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by
sirolimus, but not by
POL5551. Therefore, the inhibition of CXCR4 by
POL5551 is equally effective in preventing
neointima formation as
sirolimus, but
POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation.