title: Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling.
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.
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520;
authors.forename: Nicolas
authors.identifier: http://orcid.org/0000-0001-9893-3041
authors.initials: N
authors.lastname: Baeyens
authors.affiliation: Department of Surgery, Vascular Section, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766;
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Mulligan-Kehoe
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520;
authors.forename: Federico
authors.initials: F
authors.lastname: Corti
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520; and.
authors.forename: David D
authors.initials: DD
authors.lastname: Simon
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520;
authors.forename: Tyler D
authors.identifier: http://orcid.org/0000-0002-7872-3992
authors.initials: TD
authors.lastname: Ross
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520;
authors.forename: John M
authors.initials: JM
authors.lastname: Rhodes
authors.affiliation: Department of Surgery, Vascular Section, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766;
authors.forename: Thomas Z
authors.initials: TZ
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520;
authors.forename: Cecile O
authors.initials: CO
authors.lastname: Mejean
authors.affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520; Department of Cell Biology, Yale University, New Haven, CT 06520.
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520; and.
authors.forename: Jay
authors.initials: J
authors.lastname: Humphrey
authors.affiliation: 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.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013314:Stress, Mechanical; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D053671:Syndecan-4; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: atherosclerosis; mechanotransduction; polarity; shear stress