Research: Vascular calcification

About our research

Vascular calcification is an active and highly regulated process causing hardening of the arteries that can ultimately lead to heart attack, stroke, peripheral arterial disease and foot ulcers. It is particularly enhanced in patients with diabetes.

During vascular calcification, arterial smooth muscle cells, which normally contract and dilate to enable healthy blood vessel function, become reprogrammed into bone-related cells under conditions of inflammation, atherosclerosis and diabetes.

By understanding the mechanisms involved in the smooth muscle cell vascular calcification process, novel biomarkers and potential treatments can be developed to combat the pathological effects of the vascular mineralisation process.

Sirtuins and their role in vascular calcification in diabetes

Sirtuin proteins (SIRT) have been shown to play a role in cellular metabolism, protection against DNA damage, and longevity, all of which are associated with vascular disease.

Recent evidence demonstrates the beneficial role of SIRT1 in improved insulin sensitivity and glucose homeostasis. Our key, novel findings establish that SIRT1 activation attenuates diabetes-induced vascular calcification through the prevention of senescence or deterioration of a cell’s functional characteristics. Strikingly, we found that SIRT1 levels are decreased in both the serum and in arteries isolated from patients with diabetes and peripheral artery disease.

Academic papers

• Bartoli-Leonard, F, Wilkinson, FL, Schiro, A et al (2019) Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling. Sci Rep 9, 878 

• Ndip, A et al (2014) RANKL-OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy Diabetologia, 57, 11 

• Bartoli-Leonard, F et al (2018) The Interplay of SIRT1 and Wnt Signalling in Vascular Calcification Frontiers in cardiovascular medicine, 5, pp 183

Targeting vascular calcification using small molecule glycomimetics

Glycosaminoglycans (GAGs) are components of the extracellular matrix and act as mediators of cellular signalling. In particular, the GAG Heparan sulfate (HS), is known to be critically implicated in regulating processes such as angiogenesis, inflammation and endothelial integrity. However, studies on the potential of small molecule HS mimetics in the protection against calcification are scarce.

We have recently shown that novel small molecule glycomimetics can reduce smooth muscle cell calcification through decreasing calcium deposition, down-regulation of osteoblastic and calcification markers, and modulation of a specific (c-Met/Notch3/HES1) signalling pathway.

These studies may serve as a base for the development of new drugs for vascular calcification and ultimately, potential translation to the clinic.

Academic papers

• Mahmoud, AM, Jones, AM, Sidgwick, GP, Arafat, AM, Alexander, YM and Wilkinson, FL (2019) Small Molecule Glycomimetics Inhibit Vascular Calcification via c-Met/Notch3/HES1 Signalling Cell Physiol Biochem, 53(2), pp 323-336