Cell proliferation after balloon injury of iliac arteries in the cholesterol-fed New Zealand White rabbit.

Abstract

Acute mechanical injury of an artery results in neointimal hyperplasia that is due at least in part to cell proliferation within the vessel wall. The purpose of this study was to quantify cell proliferation activity in the iliac artery of New Zealand White rabbits after balloon injury and cholesterol feeding. Retrograde pullback balloon injury of iliac arteries was performed, and the animals were then fed a 2% cholesterol diet. At intervals from day 1 through day 35 postinjury, iliac arteries were obtained for histological analysis. Intimal and medial areas were measured morphometrically. Total number of cells within the intima and media was counted. Smooth muscle cell-predominant or macrophagepredominant regions of the intima and media were identified using HHF-35 and RAM-11 immunocytochemical markers, respectively. Number of cells in the proliferative phase of the cell cycle was measured by using the proliferating cell nuclear antigen and bromodeoxyuridine techniques. Thirty-one arteries from 16 rabbits were available for analysis. Total number of cells and number of cells per square millimeter within the media did not change significantly from day 1 through day 35 postinjury. Total number of cells within the intima increased A cute mechanical injury of the arterial vessel wall / \ results in neointimal hyperplasia. 14 The neoin-J. \ -timal formation is due, at least in part, to proliferation of cells within the medial and intimal compartments.5 " 8 This sequence of events is part of the accepted paradigm for the description of the restenosis phenomenon that occurs after angioplasty treatment in humans. 915 The New Zealand White rabbit iliac artery model of atherogenesis after acute balloon injury and cholesterol feeding has been used to study a number of facets of the response of arteries to angioplasty treatment. "20 To better understand the biological response of atherosclerotic lesions to angioplasty treatment, we studied the response of these iliac arteries to initial injury. This initial injury results in the lesions that undergo treatment by angioplasty techniques in this model. The biological response of these lesions may be influenced by the development of the initial lesion. The time course of development of intimal hyperplasia and the cellular characteristics of the iliac artery response to acute balloon injury and cholesterol feeding have beenReceived July 19, 1993; revision accepted February 8, 1994. significantly, but the number of cells per square millimeter of intima decreased significantly during the same time period. Proliferative activity was identified in the media between days 3 and 35 with peak activity at day 3 postinjury. Proliferative activity in the intima was present in all specimens from day 8 through day 35. Proliferative activity was present in both HHF-35-and RAM-11-predominant regions of the intima. Proliferative activity in the intima exceeded that in the media (/ reported. 21 The purpose of this article is to present a quantitative analysis of the cell proliferation ...

Effect of Cyclosporine on Arterial Balloon Injury Lesions in Cholesterol-Clamped Rabbits

“…In the rabbit, neointimal proliferation in arteries occurs after intimal balloon injury, 10,13,25,26 where the process is accelerated by increased plasma cholesterol levels, 25,26 as well as in cholesterol-induced atherogenesis, 7,9 and after transplantation of solid organs or arteries. 4,6,12 T lymphocytes, macrophages, and smooth muscle cells, and upregulation of VCAM-1, ICAM-1, and MHCII, are all components of these 3 types of neointimal proliferation.…”

“…4,6,12 T lymphocytes, macrophages, and smooth muscle cells, and upregulation of VCAM-1, ICAM-1, and MHCII, are all components of these 3 types of neointimal proliferation. [7][8][9][10][11][12][13] Cyclosporine has been shown to inhibit early atherosclerosis in the cholesterol-fed rabbit. 3 Furthermore, cyclosporine has been shown to inhibit development of transplant arteriosclerosis 4,5,18 and to reduce an otherwise increased occurrence of T lymphocytes, macrophages, and smooth muscle cells and upregulation of VCAM-1, ICAM-1, and MHCII in transplanted arteries.…”

“…However, the significant upregulation of cellular activation parameters such as VCAM-1, ICAM-1, and MHCII as well as proliferation of smooth muscle cells and macrophages were seen 4 to 5 weeks after balloon injury in the present study as well as in earlier studies. 10,13 Furthermore, intimal proliferation has been reported to proceed from 4 weeks up to as much as 20 weeks after balloon injury. 10,14,28 -32 Finally, cholesterol accumulation in both deendothelialized and reendothelialized areas has been reported to be an ongoing process from day 2, 33 through to day 30, 34 and up to day 119 after balloon injury.…”

“…In the transplanted artery, alloimmunity involving T lymphocytes and their consequent recruitment of macrophages seem to be of major importance 51 ; cyclosporine inhibits T lymphocytes. In the balloon-injured artery, smooth muscle cell proliferation 10,26 in response to wound healing and possibly macrophages under conditions with hypercholesterolemia 13,25,30,48 may be of more importance.…”

“…2 In experimental studies, cyclosporine has been shown to inhibit early atherosclerosis in the cholesterol-fed rabbit 3 as well as the development of transplant arteriosclerosis after immune injury. 4 -6 As the histopathological events occurring after a balloon dilatation injury have many common features with that seen after cholesterol feeding and immune injury, [7][8][9][10][11][12][13] including the presence of T lymphocytes, 10,11 it could be hypothesized that cyclosporine would also inhibit neointimal proliferation after a balloon dilatation injury. Previous studies of this hypothesis gave equivocal results 14 -16 ; however, these studies were all performed in animal models with plasma cholesterol at Ϸ0.5 to 1.5 mmol/L, levels below that seen in most humans, and in only 1 was a clinically relevant dose of cyclosporine used.…”