INVESTIGATING THE ROLE OF RRM2B THE ALTERNATIVE SUBUNIT OF RIBONUCLEOTIDE REDUCTASE IN THE ENDOTHELIUM

RRM2B is the alternative small subunit of Ribonucleotide reductase, which catalyses de novo synthesis of the deoxyribonucleotide triphosphates necessary for both nuclear DNA repair and mitochondrial DNA (mtDNA) synthesis, especially in not proliferating cells. Human syndromes and in vivo models showed that RRM2B is essential for organism survival. Mice lacking RRM2B have decreased mtDNA content, develop endothelial hypertrophy in kidney, and die for renal failure. Endothelial cells (ECs) line blood vessels and are critical regulators of vascular functions and tissue homeostasis. ECs contain low number of mitochondria, whose activity is relevant for many important endothelial functions including angiogenesis and signalling. Altered mitochondrial activity results in changes in endothelial phenotype ultimately leading to detrimental consequences in the surrounding cells. In this thesis, I investigated the role of RRM2B in the endothelium combining in vivo and in vitro approaches. In zebrafish, the rrm2b tissue-specific endothelial knock-out perturbs normal vascular development at early embryonic stages. In proliferating cultures of ECs, the downregulation of RRM2B impacts cell proliferation, migration and induces a pro-inflammatory phenotype. Interestingly, these effects parallel altered expression of PGC1-α and TFAM, two crucial regulators of mitochondrial biogenesis. Overall, these results support the hypothesis that RRM2B deficiency impacts endothelial cell behaviour.