Research Project
10429324
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.
