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Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17308-13. doi: 10.1073/pnas.1413725111. Epub 2014 Nov 17.

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling.

Author information

1
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520;
2
Department of Surgery, Vascular Section, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766;
3
Department of Biomedical Engineering, Yale University, New Haven, CT 06520; and.
4
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520; Department of Cell Biology, Yale University, New Haven, CT 06520.
5
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520; Department of Biomedical Engineering, Yale University, New Haven, CT 06520; and Department of Cell Biology, Yale University, New Haven, CT 06520 martin.schwartz@yale.edu.

Abstract

Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4(-/-)) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4(-/-) mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis.

KEYWORDS:

atherosclerosis; mechanotransduction; polarity; shear stress

PMID:
25404299
PMCID:
PMC4260558
DOI:
10.1073/pnas.1413725111
[Indexed for MEDLINE]
Free PMC Article

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