Stent endothelialization. Time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine expedition

Abstract

Background: Because prior studies have established the critical role of the endothelium in preventing vascular thrombosis and intimal thickening, we designed a series of experiments to determine the feasibility of percutaneous local catheter delivery of recombinant protein to accelerate development of an intact endothelial monolayer after stent implantation.

Methods and results: Balloon injury followed by percutaneous delivery of a 15-mm-long, balloon-expandable metallic stent was performed in 64 rabbit external iliac arteries (baseline diameter, 2.67 +/- 0.07 mm). Planimetric time-course analysis disclosed < 20% stent endothelialization at 4 days, < 40% at 7 days, and near-complete endothelialization at 28 days. The reporter protein horseradish peroxidase and the endothelial cell-specific recombinant protein vascular endothelial growth factor (VEGF) were each effectively delivered from a local delivery catheter (channel balloon catheter, ChB) after stent implantation. Although local catheter delivery (of vehicle control) itself mildly retarded the extent of stent endothelialization (10.6 +/- 2.9%) versus no local delivery (25.5 +/- 6.6%, P = .045), local ChB delivery of 100 micrograms VEGF overcame this catheter effect: By day 7, stent endothelialization was nearly complete (91.8 +/- 3.8%) (P < .0001 versus no local delivery). Consequently, stent thrombus was reduced in the VEGF-treated group (mural thrombus, 5.3 +/- 3.7%) versus no local delivery (29.3 +/- 6.8%, P = .006). Occlusive thrombus was seen only in the absence of local VEGF administration.

Conclusions: (1) Local delivery of recombinant protein to the arterial wall is feasible after stent implantation, and (2) local delivery of the endothelial cell mitogen VEGF accelerates stent endothelialization, reducing stent thrombosis. These results thus establish a novel means by which the safety and/or bioactivity of endovascular stents may be further enhanced.