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The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis.

Orr AW, Sanders JM, Bevard M, Coleman E, Sarembock IJ, Schwartz MA - J. Cell Biol. (2005)

Bottom Line: Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling.Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not.Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.

ABSTRACT
Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-kappaB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin alpha2beta1 on collagen prevents flow-induced NF-kappaB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.

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Matrix remodeling and inflammatory gene expression in vivo. C57/B6 mice were fed a chow diet (A), male ApoE  mice were fed a chow diet for 10 wk (B), and ApoE  mice were fed a Western diet for 10 wk (C). Mice were killed and the indicated arteries were removed and embedded in paraffin. Serial sections were stained for FN, FG, ICAM-1, VCAM-1, and Mac-2 and shown at high magnification, with lower magnification views of the entire vessels shown as insets.
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fig2: Matrix remodeling and inflammatory gene expression in vivo. C57/B6 mice were fed a chow diet (A), male ApoE mice were fed a chow diet for 10 wk (B), and ApoE mice were fed a Western diet for 10 wk (C). Mice were killed and the indicated arteries were removed and embedded in paraffin. Serial sections were stained for FN, FG, ICAM-1, VCAM-1, and Mac-2 and shown at high magnification, with lower magnification views of the entire vessels shown as insets.

Mentions: In C57/B6 mice fed the low fat, chow diet, sites that are susceptible to atherosclerosis in other models demonstrated focal increases in ICAM-1 and VCAM-1 staining and increased staining for FN, although no Mac-2 staining was apparent (Fig. 2 A). We did not detect any change in FG (Fig. 2 A) or LN (not depicted) staining and no staining for FN in regions outside these zones. ApoE mice fed a chow diet have elevated cholesterol and develop atherosclerotic lesions over the course of their lifespan (Daugherty, 2002). In these mice, similar colocalization of ICAM-1, VCAM-1, FN, and FG was observed when nearby sections were stained (Fig. 2 B). FN has been reported in well-defined fatty streaks (Stenman et al., 1980; Labat-Robert et al., 1985; Shekhonin et al., 1987; Tanouchi et al., 1992), but these data are the first evidence that FN is deposited before fatty streak development. In contrast, no changes in PECAM staining were evident (unpublished data). VCAM-1 staining in vascular smooth muscle cells is indicative of smooth muscle activation and is associated with atherosclerosis, which is consistent with our interpretation of these regions as early atherogenesis (Li et al., 1993).


The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis.

Orr AW, Sanders JM, Bevard M, Coleman E, Sarembock IJ, Schwartz MA - J. Cell Biol. (2005)

Matrix remodeling and inflammatory gene expression in vivo. C57/B6 mice were fed a chow diet (A), male ApoE  mice were fed a chow diet for 10 wk (B), and ApoE  mice were fed a Western diet for 10 wk (C). Mice were killed and the indicated arteries were removed and embedded in paraffin. Serial sections were stained for FN, FG, ICAM-1, VCAM-1, and Mac-2 and shown at high magnification, with lower magnification views of the entire vessels shown as insets.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171897&req=5

fig2: Matrix remodeling and inflammatory gene expression in vivo. C57/B6 mice were fed a chow diet (A), male ApoE mice were fed a chow diet for 10 wk (B), and ApoE mice were fed a Western diet for 10 wk (C). Mice were killed and the indicated arteries were removed and embedded in paraffin. Serial sections were stained for FN, FG, ICAM-1, VCAM-1, and Mac-2 and shown at high magnification, with lower magnification views of the entire vessels shown as insets.
Mentions: In C57/B6 mice fed the low fat, chow diet, sites that are susceptible to atherosclerosis in other models demonstrated focal increases in ICAM-1 and VCAM-1 staining and increased staining for FN, although no Mac-2 staining was apparent (Fig. 2 A). We did not detect any change in FG (Fig. 2 A) or LN (not depicted) staining and no staining for FN in regions outside these zones. ApoE mice fed a chow diet have elevated cholesterol and develop atherosclerotic lesions over the course of their lifespan (Daugherty, 2002). In these mice, similar colocalization of ICAM-1, VCAM-1, FN, and FG was observed when nearby sections were stained (Fig. 2 B). FN has been reported in well-defined fatty streaks (Stenman et al., 1980; Labat-Robert et al., 1985; Shekhonin et al., 1987; Tanouchi et al., 1992), but these data are the first evidence that FN is deposited before fatty streak development. In contrast, no changes in PECAM staining were evident (unpublished data). VCAM-1 staining in vascular smooth muscle cells is indicative of smooth muscle activation and is associated with atherosclerosis, which is consistent with our interpretation of these regions as early atherogenesis (Li et al., 1993).

Bottom Line: Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling.Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not.Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.

ABSTRACT
Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-kappaB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin alpha2beta1 on collagen prevents flow-induced NF-kappaB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.

Show MeSH
Related in: MedlinePlus