Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries

Background: Drug-eluting stents (DES) have been introduced successfully in clinical practice to prevent post-angioplasty restenosis. Nevertheless, concerns about the safety of DES still exist. Objective: 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 hypercholesterolaemic ApoE* 3- Leiden transgenic mice. Two weeks later these cuffs were replaced either by sirolimus- or paclitaxel-eluting cuffs. The vascular pathological effects were evaluated after two additional weeks. Results: Both anti-restenotic compounds significantly inhibited restenotic lesion progression on the atherosclerotic plaques. Vascular histopathological analyses showed that local delivery of sirolimus has no significant adverse effects on vascular disease. 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 showed an increased level of proapoptotic 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 disease. In contrast, paclitaxel at high concentration demonstrated adverse vascular pathology and transcriptional responses, suggesting a narrower therapeutic range of this potent drug. Since the use of overlapping stents is becoming more common in DES technology, this factor is important, 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.