Calciprotein Particles and the Endothelium: A Dynamic Interaction Driving Vascular Calcification

Calciprotein particles (CPPs) are calcium and phosphate containing nanocrystals associated with development of vascular calcifications (VC) in chronic kidney disease (CKD). As a consequence of a reduced kidney function in CKD, phosphate levels rise, leading to increased concentrations of CPPs in the circulation. Literature has shown that circulating CPPs induce VC in CKD, by affecting mainly the smooth muscle cells (SMCs) in the vascular wall. Nonetheless, the role of endothelial cells (ECs) in this pathological process is relatively unknown. In this thesis the relation between CPPs and ECs was investigated proposing that the endothelium is an important cell type actually driving the process of CPP-induced VC. Results in this thesis show that ECs play indeed an important role in the development of VC. ECs increase CPP-induced VC via paracrine communication with SMCs. Also, CPPs impair the metabolism of nitric oxide (NO) in ECs, reducing the endothelial-dependent relaxation of the vascular wall. As a result of CPP uptake ECs, the intracellular calcium concentration is disturbed leading to mitochondrial dysfunction and EC death. Preventing mitochondrial dysfunction using pharmaceutical interventions seems efficient to preserve endothelial survival. Translation of the preclinical findings to CKD patients showed that presence of CPPs is not only related to VC development but also vascular remodeling-related processes. Together this thesis shows that ECs play an important role in CPP-induced VC and are therefore important targets for future intervention.