Endothelial Expression of a Mononuclear Leukocyte Adhesion Molecule During Atherogenesis

Cybulsky, Myron I.; Gimbrone, Michael A.

doi:10.1126/science.1990440

Cited by 1,514 publications

(801 citation statements)

References 29 publications

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“…41 VCAM-1 has been identified as a very early event in the development of atherosclerotic lesions in experimental animal models. 42 Our results show that over time the profile of endothelial VCAM-1 mean expression, lining the whole vessel intimal circumference, did not significantly change for either apoE Ϫ/Ϫ or wild-type mice. However, endothelial VCAM-1 was highly expressed over fatty streaks and was decreased on fibrofatty and complex lesions.…”

Section: Discussionmentioning

confidence: 65%

Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet–Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E–Deficient Compared With Wild-Type Mice

Zibara

Chignier

Covacho

et al. 2000

ATVB

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Abstract-Human vascular adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and vascular cell adhesion molecule-1 (VCAM-1), are thought to play a critical role in the homing of leukocytes to sites of atherosclerotic lesions. However, very little is known about the expression of adhesion molecules in the vasculature of mice models, such as apolipoprotein E knockout (apoE Ϫ/Ϫ ) mice, the lesions of which closely mimic human atherosclerotic lesions. This study has first quantitatively characterized the mean expression of endothelial adhesion molecules, lining the whole vessel intimal circumference, over a period of time (0 to 20 weeks of diet) in aortic arch lesions of male apoE-deficient compared with wild-type (C57BL/6) mice. These animals were fed a chow or a cholesterol-rich diet. ApoE Ϫ/Ϫ animals showed first an increase (at 6 weeks) and then a reduction (at 16 weeks) in the mean expression of ICAM-1 (PϽ0.05) and PECAM-1 (PϽ0.05) but not VCAM-1 levels. Such modulation of the mean expression of adhesion molecules was not observed in wild-type mice. Confirmation of immunohistochemistry results on ICAM-1 was obtained by Northern blots performed on the aortic arch of apoE and C57BL6 chow-fed mice over a period of 20 weeks. Moreover, the presence of VCAM-1 was also confirmed at the RNA level, on aortas of control and apoE mice, by reverse transcription-polymerase chain reaction. In the second part of the study, we assayed the levels of adhesion molecules, in different types of histologically defined atherosclerotic lesions, in apoE Ϫ/Ϫ animals fed for 20 weeks. All 3 adhesion molecules (ICAM-1, PECAM-1, and VCAM-1) were observed to be reduced in fibrofatty and complex lesions but not in fatty streaks or in areas without lesions. These results indicate that the expression of these adhesion molecules in apoE-deficient animals varies with the evolution of the plaque from a fatty to a fibrous stage. (Arterioscler Thromb Vasc

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Section: Discussionmentioning

confidence: 65%

Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet–Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E–Deficient Compared With Wild-Type Mice

Zibara

Chignier

Covacho

et al. 2000

ATVB

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“…The recruitment of Mo into the inflamed arterial wall is largely due to various chemoattractant molecules, 3,4 including Mo chemoattractant protein 1, as well as others. 5 Once within the wall, the Mo differentiate into MF, which then utilize a variety of scavenger receptors such as CD36 and lectin-like oxidized low-density lipoprotein receptor-1 to bind and transport modified forms of low-density lipoprotein (LDL) into the cells. This uptake of lipids results in the hallmark cell type of atherosclerosis, the foam cell, and the accumulation of foam cells forms the core parenchyma of atherosclerotic plaque, yet another hallmark of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo

et al. 2010

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Atherosclerosis is an inflammatory disorder of arteries. Atherosclerotic plaque, in its early to intermediate stages, is composed largely of lipid-engorged foam cells. These foam cells are derived from the trafficking of monocytes (Mo) into the arterial intima, attracted to the site by chemoattractants. Given that foam cells are derived from the trafficking of Mo, the use of Netrin-1, an Mo chemorepellent, may be useful in limiting Mo accumulation and subsequent plaque formation. To investigate the potential of Netrin-1 for limiting atherosclerosis, we systemically delivered its human (h) cDNA by adeno-associated virus type 8 (AAV8, single-stranded structure) delivery into low-density lipoprotein receptor knockout (LDLRÀ/À) mice and placed the animals on a high cholesterol diet (HCD). Compared with control neomycin resistance (Neo) gene delivery/HCD, hNetrin-1 delivery resulted in a significant reduction in plaque formation, as determined by larger aortic lumen size, thinner intima-media thickness and lower blood velocity than the Neo/HCD control (all statistically significant). Indices of monocyte/macrophage (Mo/MF) accumulation, CD68, integrin, alpha M (ITGAM) and egf-like module containing, mucin-like, hormone receptor-like 1 (EMR-1), were reduced in hNetrin-1/HCD-treated animal's aortas and spleens compared with Neo/HCD-treated animals. Unexpectedly, CD25 and foxp3 (regulatory T cells (Tregs)) in the aorta were strongly upregulated. This is the first time the Mo/MF chemorepellent approach, and specific Netrin-1 gene delivery, has been performed for the reduction of Mo/MF burden and atherosclerosis. In addition, Netrin-1 has never before been linked to altered Treg levels. These data strongly suggest that hNetrin-1 gene delivery can reduce Mo/MF accumulation, inflammation and subsequent plaque formation.

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“…7 Monocytes or T-lymphocytes, in the above-described process, will be allowed to extravasate to sites of inflammation. 8 These adhesion molecules include intercellular adhesion molecule-1 (ICAM-1 or CD54), 9 platelet-endothelial cell adhesion molecule-1 (PECAM-1 or CD 31), 10 vascular cell adhesion molecule-1 (VCAM-1 or CD106), 11,12 and P-selectin (CD 62P). 13 ICAM-1, an adhesion molecule constitutively expressed by endothelial cells, has been shown to be upregulated in human atherosclerotic lesions.…”

mentioning

confidence: 99%

ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE ⁻ ^/− /ICAM-1 ⁻ ^/− ) Fed a Fat or a Chow Diet

Bourdillon

Poston

Covacho

et al. 2000

ATVB

147

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Abstract-Intercellular adhesion molecule (ICAM)-1, a major adhesion molecule, plays a critical role in the homing of leukocytes to sites of atherosclerotic lesions. However, very little is known on the role of ICAM-1 in initiating and perpetuating vascular lesions in ApoE Ϫ/Ϫ mice fed a chow or a fat diet. This study has investigated the mean aortic lesions in mice (C57BL6 background) with a single-knockout (ApoE Ϫ/Ϫ ) or double-knockout (DKO; ApoE Ϫ/Ϫ , ICAM-1 Ϫ/Ϫ ) fed a chow or a fat diet over a period of 3, 6, 15, and 20 weeks. A 3-fold reduction in lesion size was observed at all time points in DKO mice fed a chow diet. However, in DKO mice fed a fat diet, a marked reduction in the aortic lesion was observed at 3 and 15 weeks, which did not reach a significant level at 6 and 20 weeks. This study shows in essence that DKO mice are protected from developing significant lesions for up to 6 weeks when fed a chow diet and from 3 to 6 weeks when fed a fat diet. After 6 weeks, the lesion size of the DKO mice follows that of the single-knockout mice when fed a chow diet and gets to the same level in mice fed a fat diet. Plasma cholesterol levels were not altered as a result of ICAM-1 deficiency. These studies show that ICAM-1 is implicated in the formation and progression of atherosclerotic lesions.

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Endothelial Expression of a Mononuclear Leukocyte Adhesion Molecule During Atherogenesis

Cited by 1,514 publications

References 29 publications

Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet–Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E–Deficient Compared With Wild-Type Mice

Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet–Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E–Deficient Compared With Wild-Type Mice

Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo

ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE ⁻ ^/− /ICAM-1 ⁻ ^/− ) Fed a Fat or a Chow Diet

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Endothelial Expression of a Mononuclear Leukocyte Adhesion Molecule During Atherogenesis

Cited by 1,514 publications

References 29 publications

Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet–Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E–Deficient Compared With Wild-Type Mice

Modulation of Expression of Endothelial Intercellular Adhesion Molecule-1, Platelet–Endothelial Cell Adhesion Molecule-1, and Vascular Cell Adhesion Molecule-1 in Aortic Arch Lesions of Apolipoprotein E–Deficient Compared With Wild-Type Mice

Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo

ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE − /− /ICAM-1 − /− ) Fed a Fat or a Chow Diet

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ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE ⁻ ^/− /ICAM-1 ⁻ ^/− ) Fed a Fat or a Chow Diet