Vessel calcifications are a main risk factor for the development of cardiovascular diseases, a leading cause of morbidity and mortality in western societies. Even though vascular calcifications have been researched for centuries, patients still suffer from a huge therapeutic gap, because neither an effective prophylaxis, nor an effective treatment is available. Currently, consent exists that vascular calcification is an active cellular process that resembles bone formation. Vascular Smooth Muscle Cells (VSMCs) and their transdifferentiation into osteoblast like cells are considered decisive in the formation of vascular calcifications. Several stimuli can induce osteoblastic transdifferentiation, including cellular aging processes, oxidative stress and inflammation. These factors can be linked into a concept termed inflammaging via the formation of damage associated molecular patterns, persistent DNA damage and induction of a senescence associated secretory phenotype. The objective of this dissertation was to analyse the effects of the cellular stressors Azathioprine and Doxorubicin and the pro-inflammatory cytokine interleukin 1ß on the induction of osteoblastic transdifferentiation of VSMCs and vascular calcification in different experimental settings. The cellular stressors induce the formation of reactive oxygen species, cellular senescence, secretion of pro-inflammatory cytokines such as interleukin 1ß and interleukin 6, upregulation of NLRP3 inflammasome components as well as osteoblastic transdifferentiation and calcification of VSMCs. Stimulation with interleukin 1ß induced a pro-inflammatory auto-loop, osteoblastic transdifferentiation and calcification of VSMCs, but did not induce markers of senescence in VSMCs apart from components of the cellular senescence associated secretory phenotype. For both, cellular stressors and interleukin 1ß, the NLRP3 inflammasome is decisively involved in the calcification process, as inhibition of NLRP3 significantly reduces the calcification induced by cellular stressors and interleukin 1ß. This dissertation is in line with other recent research that emphasizes the involvement of inflammaging in the pathology of vascular calcification. Several therapeutic targets arise from the insight that oxidative stress, inflammation and senescence are crucially involved in the pathophysiology of VSMC calcification. These new therapeutic approaches can help to meet the high unmet clinical need of patients suffering from vascular calcifications.
