Endothelial progenitor cell response to antiproliferative drug exposure.

Banerjee, Subhash; Xu, Hao; Fuh, Eric; Nguyen, Kytai T; Garcia, Joseph A; Brilakis, Emmanouil S; Bhatt, Deepak L

BACKGROUND Vascular stent coverage by endothelial cells, derived from endothelial progenitor cells (EPC) is considered a surrogate for healing. However, the effects of antiproliferative drugs used in current drug-eluting stents (DES) on EPC proliferative and antithrombotic function remains poorly defined. METHOD AND RESULTS Herein, we studied and compared the in vitro and in vivo effects of four antiproliferative drugs - paclitaxel, sirolimus, everolimus, and zotarolimus on several EPC properties including colony forming units (CFU), cell proliferation, apoptosis, antithrombotic and prothrombotic gene expression and nitric oxide (NO) as well as prostacyclin (PGI(2)) release. We also examined EPC migration and adhesion under flow conditions. We find that whereas all antiproliferative agents inhibited EPC proliferation and caused cell apoptosis, only paclitaxel and sirolimus reduced CFU formation. Paclitaxel treatment also resulted in the greatest down-regulation of antithrombotic gene expression and up-regulation of prothrombotic gene expression. NO release, migration, and adhesion of EPC under shear stress were inhibited by all antiproliferative drugs, most notably by paclitaxel and sirolimus. CONCLUSIONS These results indicate that antiproliferative drugs on DES, particularly paclitaxel, impair the proliferative and antithrombotic functions of EPC, and thereby could contribute to incomplete vascular healing and increase the risk of stent thrombosis.