Asymmetric dimethylarginine (ADMA) signalling via the calcium sensing receptor in cardiometabolic disease

Asymmetric dimethylarginine (ADMA) is an established risk factor for cardiovascular disease and is elevated in individuals with hypertension, coronary heart disease and obesity.

ADMA is a competitive antagonist of nitric oxide synthase (NOS); thus, high concentrations reduce NO production, a critical mediator of vascular function.

Recently we have identified a second pathway for ADMA via the Calcium sensing receptor (CaSR), where physiological concentrations of ADMA potentiate CaSR signalling.

CaSR is expressed in both endothelial and smooth muscle cells where it plays opposing roles in vasodilation and constriction.

The aim of this study is to elucidate the role of CaSR in the vasculature and to understand how ADMA modulates the balance of CaSR vascular regulation in health and how this is altered in obesity.

CaSR function will be interrogated using both pharmacological agents and a novel transgenic mouse strain – endothelial specific CaSR deletion. These will be utilised in cell culture, ex vivo myography and in vivo telemetry studies.

Finally, a model of diet induced obesity will be used to dissect the role of endothelial ADMA:CaSR signalling on cardiometabolic phenotypes.

On conclusion, these studies will inform whether ADMA:CaSR signalling is a viable clinical target for cardiovascular disease.