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.
Highlights
The endothelial glycocalyx extends into the arterial lumen and experiences shear forces from blood flow
Using endothelial cells isolated from sdc-1 knock-out mice, we demonstrate that sdc-1 is required for the activation of Akt and RhoA and for the formation of a phosphorylation gradient in paxillin in the initial stages of the endothelial response to shear stress
Loss of Syndecan-1 in Endothelial Cells Inhibits the Activation of Akt in Response to Shear Stress—Shear stress rapidly activates the Akt pathway in endothelial cells leading to alterations in oxidative stress [31], suppression of apoptotic signaling pathways [32], and production of NO [33]
Summary
The endothelial glycocalyx extends into the arterial lumen and experiences shear forces from blood flow. 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. Removal of heparan sulfate glycoaminoglycans from the cell surface using enzymatic digestion reduces endothelial production of vasodilatory factors in response to shear stress [15] It is unknown which proteoglycans are important in these processes, as well as their scope of mechanistic involvement in mechanosensing of shear stress. Sdc-1 knock-out profoundly alters the shear stress-induced expression of transcription factors, vasodilatory mediators, and inflammatory soluble factors and receptors Based on these findings, we propose that sdc-1 is an important atheroprotective molecule that governs both the inflammatory state of the endothelial cells and the induction of atheroprotective phenotypes by shear stress. This work expands our limited understanding of the role of cell surface proteoglycans in vascular mechanobiology and may provide insight into the mechanisms of shear stress-mediated regulation of atherogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
