Sirolimus and Paclitaxel Provoke Different Vascular Pathological Responses after Local Delivery in a Murine Model for Restenosis on Underlying Atherosclerotic Arteries

Nuno M M Pires ¹, Daniel Eefting ¹, Margreet R de Vries ¹, Paul H A Quax ¹ and J W Jukema ^2*

¹ TNO-Quality of Life, Netherlands
² Leiden University Medical Center, Netherlands

^* To whom correspondence should be addressed. E-mail: j.w.jukema{at}lumc.nl.

Accepted 6 March 2007

Abstract

Objective Drug-eluting stents (DES) have been introduced successfully in clinical practice to prevent post-angioplasty restenosis. Nevertheless, DES safety-related concerns still exist. We sought to investigate the vascular pathology and transcriptional responses to sirolimus and paclitaxel in a murine model for restenosis on underlying diseased atherosclerotic arteries.

Methods Atherosclerotic lesions were induced by placement of a perivascular cuff around the femoral artery of hypercholesterolemic ApoE*3-Leiden transgenic mice. Two weeks later these cuffs were replaced either by sirolimus- or paclitaxel-eluting cuffs. Evaluation of the vascular pathological effects was assessed after two additional weeks.

Results Both anti-restenotic compounds significantly inhibited restenotic lesion progression on the atherosclerotic plaques. Vascular histopathological analyses revealed that local delivery of sirolimus has no significant adverse effects on vascular pathology. Conversely, high dosages of paclitaxel significantly increased apoptosis, internal elastic lamina disruption, and decreased medial and intimal smooth muscle cells and collagen content. Moreover, transcriptional analysis by real-time RT-PCR revealed an increased level of pro-apoptotic mRNA transcripts (FAS, BAX, Caspase 3) in paclitaxel-treated arteries.

Conclusions Sirolimus and paclitaxel are effective in preventing restenosis. Sirolimus has no significant effect on arterial pathology. In contrast, paclitaxel demonstrated at high concentration adverse vascular pathology and transcriptional responses suggesting a narrower therapeutic range of this potent drug. Since the use of overlapping stents becomes more common in DES technology, this issue is of importance given that higher dosages of paclitaxel may lead to increased apoptosis in the vessel wall and consequently to a more unstable phenotype of the pre-existing atherosclerotic lesion.

Keywords: Animal model, Atherosclerosis, Pathology, Restenosis, Stents

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