A novel rat model of carotid artery stenting for the understanding of restenosis in metabolic diseases

Abstract

The effects of risk modifiers such as diabetes, obesity and hypertension on vascular healing after stent deployment are largely unknown, because of a lack of an appropriate animal model to study. Since many inbred strains of rats expressing these phenotypes are available, we validated a carotid artery model of in-stent restenosis in the rat. A detailed histomorphometric analysis was performed on 2-cell Multi-Link(TM) stents (1.5 x 5 mm) deployed in the common carotid artery of male Wistar rats. Early focal thrombus formation around stent struts with adherent leukocytes was evident by day 3. The number of ED-1-positive macrophages was maximal by day 7 and declined markedly thereafter. Neointimal cell proliferation peaked by day 7 (19.3 +/- 6.9) and progressively decreased to <2% by day 60. By day 14, neointimal area was significantly increased (0.39 +/- 0.03 vs. 0.18 +/- 0.05 mm(2) at day 7, p = 0.003) characterized by an enhanced number of alpha-actin-positive smooth muscle cells surrounded by extracellular matrix rich in versican and hyaluronan. At day 28, neointimal area was maximal accompanied by an appreciable decrease in the staining intensity for hyaluronan and versican. By day 60, neointimal area decreased significantly (0.28 +/- 0.04 vs. 0.45 +/- 0.07 mm(2) at day 28, p = 0.04) independent of a change in cell density. This regression phase was accompanied by a marked increase in elastin fibrils and collagen type I. In summary, vascular healing following carotid artery stenting in the rat parallels that of larger animals; however, it is accelerated relative to humans.