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 porcine 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.