Project Summary
With increased age and/or hypertension, arteries lose elasticity and thicken, giving rise to a stiffened arterial wall. Arterial
stiffness is a key underlying risk factor and is a hallmark of age/hypertension-related cardiovascular diseases such as
atherosclerosis. Endothelial cell (EC) dysfunction, characterized by increased proliferation, permeability and inflammation
is at the heart of the mechanism driving vascular diseases. ECs lining the vasculature are highly responsive to mechanical
forces and respond to these external forces by altering gene expression and downstream signaling pathways. In the
vasculature, disturbed blood flow patterns promote the expression of pro-inflammatory, pro-proliferative genes leading
to EC dysfunction and atherosclerosis. The glycocalyx is a glycan complex that is expressed on the surface of EC and is
known to function as a mechanosensor that translates external forces into genetic and functional changes in EC. The
glycocalyx is a vital element of a functional endothelium, where it regulates EC homeostasis and integrity. Intriguingly, at
athero-prone regions, disturbed blood flow promotes loss of the glycocalyx, leading to EC dysfunction. Additionally, in
hypertensive mice, the expression of proteins in synthetic pathways for glycocalyx components are reduced. These
observations suggest that there is a correlation between the expression of glycolcayx components with the development
of hypertension. Whilst stiffness-mediated tension is another mechanical force that promotes EC dysfunction and vascular
disease, it is not known whether the effects of stiffness are translated into genetic and cellular changes through the
glycocalyx machinery. Consistent with this, the effect of hypertension on the glycocalyx has not been reported to date.
Preliminary work from our lab has demonstrated that glycocalyx expression is reduced on the surface of EC cultured on
stiff polyacrylamide gels (10 kPa, mimicking physiological stiffness of aged/hypertensive arteries) vs. EC cultured on soft
gels (2.5 kPa, mimicking physiological stiffness of young/normotensive arteries), indicating that increased stiffness inhibits
glycocalyx expression. Taken together, here we hypothesize that age/hypertension-related increases in arterial stiffness
reduce glycocalyx expression from ECs, leading to EC dysfunction and vascular disease.