Both Apolipoprotein E and Immune Deficiency Exacerbate Neointimal Hyperplasia After Vascular Injury in Mice

Zhu, Bing; Reardon, Catherine A.; Getz, Godfrey S.; Hui, David Y.

doi:10.1161/hq0302.105377

Cited by 29 publications

(27 citation statements)

References 41 publications

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“…24 -27 In contrast, interferon-␥ secreted by lymphocytes was found to inhibit arterial stenosis after injury, 28 and immune cell deficiency was found to exacerbate injury-induced neointimal hyperplasia in mice. 29 Results from the present study also indicate that susceptibility to injury-induced neointimal hyperplasia is dictated by at least 2 recessive genes. This conclusion is derived from the following experiments: First, all of the F 1 hybrid mice from the C57BL/6 and C57L/J intercross were resistant to neointimal hyperplasia, which suggests that resistance is the dominant trait.…”

Section: Discussionsupporting

confidence: 59%

Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice

Kuhel

Zhu

Witte

et al. 2002

ATVB

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Abstract-Five inbred strains of mice differing in susceptibility to diet-induced atherosclerosis were compared for neointimal hyperplasia after endothelial denudation with an epoxy resin-modified catheter probe. Results showed that all animals responded similarly to the arterial injury, with increased medial area and thickness after 14 days. In contrast, a significant strain-specific difference in neointimal formation after injury was observed. The atherosclerosis-susceptible C57L/J mice were also susceptible to injury-induced neointimal hyperplasia, and the C3H mice were resistant to both forms of vascular diseases. The 129/Sv mice, which displayed an intermediate level of diet-induced atherosclerosis, also displayed an intermediate level of injury-induced neointimal hyperplasia. Interestingly, the atherosclerosis-susceptible C57BL/6 mice were resistant to neointimal hyperplasia after endothelial denudation, whereas the atherosclerosis-resistant FVB/N mice were susceptible, displaying massive neointimal hyperplasia after arterial injury. All (C57L/ JϫC57BL/6)F 1 hybrid mice were resistant to injury-induced neointimal hyperplasia. Moreover, N 2 mice generated from backcrossing the F 1 hybrid mice to the susceptible C57L/J mice displayed a range of arterial response to injury, spanning the most severe to the most resistant phenotype. These results indicate that injury-induced neointimal hyperplasia and diet-induced atherosclerosis are controlled by distinct sets of genes; the former appeared to be determined by recessive genes at Ն2 loci.

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Section: Discussionsupporting

confidence: 59%

Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice

Kuhel

Zhu

Witte

et al. 2002

ATVB

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“…After a recovery period of 14 days, mice were euthanized and whole necks were dissected and fixed for sectioning. Morphometric analysis of the histology data revealed minimal neointima in the C57BL/6 mice, compared with the neointima size of apoE Ϫ / Ϫ mice 14 days after endothelial injury reported previously (8,17). The iNOS-defective C57BL/6 mice ( NOS2 Ϫ / Ϫ ) also showed only minimal neointima area after endothelial denudation.…”

Section: Resultssupporting

confidence: 50%

Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase

Moore

Hui

2005

Journal of Lipid Research

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Previous studies have shown apolipoprotein E (apoE) recruitment to medial layers of carotid arteries after vascular injury in vivo and apoE activation of inducible nitric oxide synthase (iNOS) in smooth muscle cells in vitro.This investigation explored the relationship between medial apoE recruitment and iNOS activation in protection against neointimal hyperplasia. ApoE was present in both neointimalresistant C57BL/6 mice and neointimal-susceptible FVB/N mice 24 h after carotid denudation, but iNOS expression was observed only in the neointimal-resistant C57BL/6 mice. However, iNOS was not observed in apoE-defective C57BL/6 mice. In contrast, overexpression of apoE in FVB/N mice activated iNOS expression in the injured vessels, resulting in protection against neointimal hyperplasia. ApoE and iNOS were colocalized in the medial layer of neointimalresistant mouse strains. Endothelial denudation of carotid arteries in the iNOS-deficient NOS2 ؊ / ؊ mice did not increase neointimal hyperplasia but significantly increased medial thickness and area. The iNOS-specific inhibitor also abrogated the apoE protective effects on vascular response to injury in apoE-overexpressing FVB/N mice. Thus, injuryinduced activation of iNOS requires apoE recruitment. Moreover, both apoE and iNOS are necessary for the suppression of cell proliferation, and apoE recruitment without iNOS expression resulted in medial hyperplasia without cell migration to the intima. Neointimal hyperplasia is a critical pathological process in several vascular occlusive diseases, including atherosclerosis, vein graft-induced arteriosclerosis, and the restenotic response to angioplasty and stent placement (1-4). The key cause of its pathology is endothelial damage, which exposes the underlying smooth muscle cells in the media to cytokines, growth factors, and other plasma components in the circulation, resulting in a loss of contractile characteristics and adoption of a synthetic phenotype (5, 6). Phenotypic activation of the underlying smooth muscle cells results in their migration from the media to the intima, where their proliferation and increased synthetic potential lead to the formation of the occlusive neointima (7).Recent studies in mice have shown that one determinant regulating the severity of neointimal formation is the level of apolipoprotein E (apoE) in the circulation. Results of these studies showed that transgenic overexpression of apoE is protective and that apoE gene ablation exacerbates neointimal hyperplasia caused by mechanically induced endothelial denudation (8). In fact, subphysiological levels of apoE were shown to have beneficial effects in limiting neointimal hyperplasia without correcting for hypercholesterolemia in apoE-null mice (9). The protective role of apoE has been established to involve the recruitment of circulating apoE to the medial layers of the injured vessel (10). It is likely that apoE interaction with the medial smooth muscle cells limits their migration and proliferation in response to growth factors prese...

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“…Nevertheless, rampant neointimal hyperplasia was consistently observed in the apoE knockout mice. 13,14 Thus, the infiltra- tion of HDL to the vessel wall after endothelial denudation is not sufficient, and the presence of apoE is required, for protection against injury-induced neointimal hyperplasia. Previous studies have documented the ability of arterial smooth muscle cells to synthesize apoE in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…9 -12 In mouse models, apoE has been shown to modulate the vascular response to injury in vivo. 13,14 Mice in which the apoE gene has been knocked out show an exacerbated response to endothelial denudation compared to wild-type. In contrast, transgenic mice with liver overexpression of the human apoE gene show a decreased response to vascular injury in the form of neointimal hyperplasia.…”

mentioning

confidence: 99%

Vascular Apolipoprotein E Expression and Recruitment from Circulation to Modulate Smooth Muscle Cell Response to Endothelial Denudation

Moore

Zhu

Kuhel

et al. 2004

The American Journal of Pathology

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Apolipoprotein E (apoE) has been shown previously to have anti-proliferative and anti-migratory effects on smooth muscle cells in culture. In addition, overexpression of the apoE gene also reduces neointimal hyperplasia in mice after endothelial denudation. In this investigation, immunohistochemical techniques were used to demonstrate that apoE was present in the medial smooth muscle layers of the carotid artery between 1 and 28 days after endothelial cell denudation. Analysis of transgenic mice overexpressing human apoE in the liver revealed that apoE was recruited from the circulation to the injured site of the vessel wall. In situ hybridization using a mouse-specific apoE mRNA probe confirmed that apoE was also synthesized in the carotid artery after endothelial denudation. Interestingly, apoE accumulation in apoE transgenic mice followed a layer-specific pattern, and was inversely associated with smooth muscle ␣-actin expression. The vascular accumulation of apoE after endothelial denudation, and its assocation with ␣-actin-depleted smooth muscle cells, suggest that apoE inhibition of injury-induced neointimal hyperplasia is not due to the inhibition of injury-induced smooth muscle cell de-differentiation, but is likely a direct effect of apoE on smooth muscle cell migration and proliferation.

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Both Apolipoprotein E and Immune Deficiency Exacerbate Neointimal Hyperplasia After Vascular Injury in Mice

Cited by 29 publications

References 41 publications

Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice

Distinction in Genetic Determinants for Injury-Induced Neointimal Hyperplasia and Diet-Induced Atherosclerosis in Inbred Mice

Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase

Vascular Apolipoprotein E Expression and Recruitment from Circulation to Modulate Smooth Muscle Cell Response to Endothelial Denudation

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