Glycocalyx Regeneration to Heal Vascular Inflammation and Atherosclerosis

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Project Summary: Atherosclerosis – a precursor to coronary artery disease and heart attack, stroke, aneurysm, peripheral vascular disease, and retinal vascular disease – is a condition in which artery walls become eroded, which makes them permeable to inflammatory lipids and cells that form disruptive plaques. Onset of inflammation and atherosclerosis is recognized to coincide with inner blood vessel endothelium shedding of its vasculoprotective glycocalyx coat. The glycocalyx is a sugar-rich layer that lines the inner blood vessel wall and is largely composed of glycosaminoglycans, primarily heparan sulfate (HS) and hyaluronan. Glycocalyx loss disables endothelium function and protection against unwanted molecular and cellular infiltration from the flowing blood. At present, common cardiovascular medicines include lipid lowering and anti-platelet drugs. There is a need for treatments that clinically restore endothelial glycocalyx to treat vascular disease, given that glycocalyx integrity is at the front-line in combating atherosclerosis onset and progression. Recently, there has been new development of therapies to promote glycocalyx health in order to reverse endothelium dysfunction, inflammation, and atherosclerosis. Our research group is contributing to this effort by developing a novel chemical formulation comprised of exogenous mucosal HS and sphingosine-1-phosphate (S1P). We previously reported that this formulation can be used in cell culture experiments to repair degraded endothelial glycocalyx and subsequently to restore transendothelial barrier function (Cheng et al., Int J Nanomedicine, 2016) and interendothelial communication (Mensah et al., PLoS One, 2017). To our knowledge, we are the first group to achieve functional glycocalyx regeneration in cultured endothelial cells. The envisioned project will build upon our previous findings. We intend to further assess feasibility and perform mechanism-of-action studies in endothelial cells cultured in a parallel plate chamber setting in which we can manipulate the fluid and/or chemical environment to model pro-atherosclerotic conditions. This system has commonly been used to test the ability of new drug treatments to mitigate dysfunction and pro-atherosclerotic risk factors in endothelial cells. In Aim 1, we will conjugate, characterize, and optimize the exogenous HS and S1P formulation and test its efficacy and mechanism-of-action in repairing damaged glycocalyx, in the onset of pro-atherosclerotic endothelial dysfunction. Aim 2 will evaluate the ability of glycocalyx reinforcement to attenuate the severity of endothelium hyper-permeability and other endothelial phenotype changes that occur in the early stages of atherosclerosis. This work will lay the foundation for future preclinical in vivo studies and subsequent clinical efforts to further develop the formulation and its utilization.