Summary
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.
Keywords
Restenosis - stents - vascular remodelling - chemokines
