Cell-Matrix Signalling during Vascular Calcification

Cardiovascular diseases remain a leading cause of mortality in the western world. A higher cardiovascular risk has been associated with the development of calcification in the medial layer of the arteries. This type of calcification occurs especially during aging and is accelerated in chronic kidney disease and diabetes mellitus. The development of medial vascular calcification has been considered an active and regulated process, which is modulated by vascular smooth muscle cells. These cells are able to transform into cells with some bone- forming properties and can thereby augment an active calcification process in the vascular tissue. However, many gaps remain in the understanding of the mechanisms underlying the pro-calcific transformation of vascular smooth muscle cells. An altered communication of vascular smooth muscle cells with the extracellular matrix could be an important signalling event during vascular calcification. In pilot studies, we observed a pro-calcific effect of a stress-associated extracellular matrix signalling molecule on vascular smooth muscle cells. The aim of the current project is to study in detail the relevance and effects of extracellular matrix signalling molecules and their pathways during vascular smooth muscle cell calcification. Therefore, we will investigate the effects of these transmitters in vascular smooth muscle cell calcification models. Furthermore, we will elucidate the activated downstream signalling events, linking these transmitters and receptors to cellular calcification pathways. In addition, we will determine whether inhibition of these pathways may ameliorate vascular calcification and whether hallmarks of these pathways are altered in human patients with high risk for calcification. This project will shed new light on how pro-calcific signals are sensed and relayed to calcification pathways in vascular smooth muscle cells, which will advance the understanding of the complex mechanisms during vascular calcification. These observations could be of translational relevance, since the signalling pathways studied within this project may be directly accessible for therapeutic interventions. The insights from this project could be a step towards new therapeutic concepts to reduce cardiovascular mortality.