The Role of syndecan-1 in flow-mediated endothelial mechanotransduction
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Cardiovascular disease kills over 750,000 people in the United States and an estimated 17.3 million people worldwide each year. Atherosclerosis, the formation of lipid-rich plaques in the walls of blood vessels, is the primary driver of complications in cardiovascular disease. These plaques partially or totally occlude downstream blood flow, resulting in ischemia and in peripheral limbs can require amputation. Alternatively, they can develop a vulnerable ‘fibrous cap’ phenotype that is susceptible to rupture, leading to a massive thrombotic cascade that can cause stroke or myocardial infarction. Current treatments predominately focus on either physically opening the blood vessels (e.g. balloon catheters and stenting) or creating bypass grafts. These treatments, however, frequently need to be repeated, particularly if patients do not change their dietary and exercise protocols. Therefore, a new approach to treating atherosclerosis that targets the mechanisms that drive vessels towards a pathogenic phenotype could be extremely helpful for preventing disease. Endothelial cells line blood vessels and are the principle cells responsible for interactions between blood flow and the surrounding tissue. In addition to providing a barrier, they are capable of sensing the mechanical forces induced by the blood flow. This sensing mechanism is responsible for driving their phenotype between an ‘atheroprotective’ or ‘atheroprone’ state; specifically, steady laminar shear stress results in ‘healthy’ endothelial cells while low or oscillatory shear stresses induces an inflammatory phenotype. While research has been conducted to look at the effects of shear stress on endothelial cells, the initial sensing mechanism that drives these downstream pathways remains unclear. Here we investigate the heparan sulfate proteoglycan syndecan-1 as a potential upstream regulator of these changes. Using custom-built shear stress application devices, we show that endothelial cells lacking syndecan-1 have a reduced response to shear stress and a general increase in inflammatory state. In vivo studies in a knockout mouse model extend these results; syndecan-1 knockout mice have more pronounced inflammatory responses and an increase in leukocyte-binding proteins in low shear conditions. These findings illustrate syndecan-1 as a potential target for future therapeutics aimed at driving potentially vulnerable vasculature away from a pathogenic phenotype.