title: Loss of syndecan-1 induces a pro-inflammatory phenotype in endothelial cells with a dysregulated response to atheroprotective flow.
abstract: Fluid shear stresses are potent regulators of vascular homeostasis and powerful determinants of vascular disease progression. The glycocalyx is a layer of glycoaminoglycans, proteoglycans, and glycoproteins that lines the luminal surface of arteries. The glycocalyx interacts directly with hemodynamic forces from blood flow and, consequently, is a prime candidate for the mechanosensing of fluidic shear stresses. Here, we investigated the role of the glycocalyx component syndecan-1 (sdc-1) in controlling the shear stress-induced signaling and flow-mediated phenotypic modulation in endothelial cells. We found that knock-out of sdc-1 abolished several key early signaling events of endothelial cells in response to shear stress including the phosphorylation of Akt, the formation of a spatial gradient in paxillin phosphorylation, and the activation of RhoA. After exposure to atheroprotective flow, we found that sdc-1 knock-out endothelial cells had a phenotypic shift to an inflammatory/pro-atherosclerotic phenotype in contrast to the atheroprotective phenotype of wild type cells. Consistent with these findings, we found increased leukocyte adhesion to sdc-1 knock-out endothelial cells in vitro that was reduced by re-expression of sdc-1. In vivo, we found increased leukocyte recruitment and vascular permeability/inflammation in sdc-1 knock-out mice. Taken together, our studies support a key role for sdc-1 in endothelial mechanosensing and regulation of endothelial phenotype.
authors.affiliation: From the Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas 78712 and.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Voyvodic
authors.forename: Daniel
authors.initials: D
authors.lastname: Min
authors.forename: Robert
authors.initials: R
authors.lastname: Liu
authors.forename: Evan
authors.initials: E
authors.lastname: Williams
authors.forename: Vipul
authors.initials: V
authors.lastname: Chitalia
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Dunn
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Baker
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001783:Blood Flow Velocity; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D019276:Glycocalyx / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C508242:Sdc1 protein, mouse; D053668:Syndecan-1
keywords: Atheroprotective Flow; Endothelial Cell; Flow; Glycocalyx; Inflammation; Leukocyte; Mechanotransduction; Shear Stress; Syndecan-1