Grant: Operating Grant

The cells lining blood vessels are called endothelial cells and they are crucial in the control of blood pressure and vascular tone. Intracellular Ca2+ ions are key signalling molecules and are essential to endothelial cell functions that control vascular tone. Our lab focuses on fundamental mechanisms involving intracellular Ca2+ and endothelial regulation of vascular function. We have recently identified a unique Ca2+ signalling pathway in endothelium that is spontaneous and spatially restricted, and which we termed "Ca2+ pulsars". This novel Ca2+ signal has been shown to activate proteins at the cell membrane called ion channels and is suggested to be involved in regulation of vascular function. Calmodulin Kinase II (CaMKII) is an enzyme characterized by its unique ability to detect and interpret intracellular calcium signals in neurons and cardiac muscle cells. Interestingly, CaMKII appear to be involved in both endothelial function and dysfunction. However, the mechanisms underlying activation and regulation of CaMKII in endothelium remain to be established. Therefore, we seek to determine the relationship between Ca2+ pulsars, the activation of CAMKII and their combined roles in vascular function. State-of-the-art confocal microscopy on living tissue and novel fluorescent probes will be used in conjunction with challenging electrophysiological approaches to assess the impact of CaMKII and Ca2+ pulsars on membrane potential of vascular cells, therefore on vascular function. Pathological alterations regarding the relationship between Ca2+ pulsars and CaMKII will be studied using a mouse model of hypertension. Our work will provide novel insights on key mechanisms underlying the regulation of CaMKII and its involvement in endothelial function and dysfunction. This research may provide crucial information regarding therapeutic targets for vascular disease such hypertension.