Incidence of intimal proliferation and apoptosis following balloon angioplasty in an atherosclerotic rabbit model

Objective: The aim of this study was to determine the occurrence of apoptosis in relation to the proliferative response in the intimal layer after experimental balloon angioplasty of a pre-existing plaque. Methods: After induction of an intimal plaque in the right carotid artery by electrical stimulation, 26 rabbits underwent balloon angioplasty. Twelve animals served as a control group without performance of angioplasty after plaque induction. To study the time course of intimal apoptosis and cell proliferation the vessels were excised on day 7, 14 and 28 after balloon angioplasty. For in situ detection of apoptosis, the TUNEL-technique (TdT-mediated d-UTP fluorescein nick end labeling) was used. In addition, brornodeoxyuridine labeling in all animals allowed the determination of the percentage of cells undergoing DNA synthesis in the neointimal area. Additionally, smooth muscle cells were detected by immunostaining of cr-actin and macrophages by a specific antibody (RAM Il). Results: Within 28 days of balloon angioplasty, the number of cells undergoing apoptosis remained at a very low level and was not significantly different to the control group without interventional treatment (controls: 0.1 +/- 0.15%; 7 days: 0.44 +/- 0.68%; 14 days: 0.13% +/- 0.11%; 28 days: 0.1 +/- 0.1%). In contrast, the number of cells undergoing DNA synthesis was significantly increased at day 7 after angioplasty (3.72 +/- 2.0% vs. 0.51 +/- 0.29% in controls), resulting in an increase of the total intimal area from 0.088 +/- 0.037 mm(2) in the control animals up to 0.256 +/- 0.172 mm(2) at day 28 following balloon dilatation. Conclusions: Our data showed that significant changes in the occurrence of apoptosis are not involved in the regulation of cellular turnover during the examined time period after vessel wall injury. The lacking up-regulation of apoptosis in comparison to the increased cell proliferation in order to maintain the tissue balance is perhaps an important regulatory mechanism leading to intimal hyperplasia after vascular injury in this animal model. Overall, we suggest that there may be a delicate balance between cell proliferation and apoptosis in smooth muscle cells of the vessel wall, and only small shifts in this balance could account for both cellular accumulation in restenotic lesions as well as cell death in mature atheroma. (C) 2000 Elsevier Science B.V. All rights reserved.