Loss of Syndecan-1 Induces a Pro-Inflammatory Phenotype in Endothelial Cells with a Dysregulated Response to Atheroprotective Flow [Molecular Bases of Disease]

February 19th, 2014 by Voyvodic, P. L., Min, D., Liu, R., Williams, E., Chitalia, V., Dunn, A. K., Baker, A. B.

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 knockout 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 knockout 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 knockout 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 knockout mice. Taken together, our studies support a key role for sdc-1 in endothelial mechanosensing and regulation of endothelial phenotype.
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