Long non‐coding RNAs and RNA binding proteins in endothelial cell function

The endothelium is crucial for the controlled exchange of cells and molecules, the regulation of blood pressure and the creation of new vasculature. Upon aging there is a gradual decrease in cellular function, and this is also observed in endothelial cells. Dysfunction of the endothelium can contribute to cardiovascular diseases such as hypertension and atherosclerosis, and aging is among the most important risk factors for this. In this thesis we further investigate how the function of the endothelial cells is regulated. More specifically, we investigate long non-coding RNAs (lncRNA) and RNA binding proteins. LncRNAs are transcribed, but not translated into protein. To better understand the role of lncRNAs in endothelial cells, we inhibited their expression in vitro and assessed endothelial barrier, proliferation and angiogenic sprouting. LncRNA MEG8 was found to regulate both sprouting and the endothelial barrier, through distinct mechanisms. LncRNA AERRIE was found to be regulated during endothelial to mesenchymal transition. Expression of AERRIE was not necessary for the induction of this process, but was found to regulate SULF1, which is known to regulate TGF-β signalling. Finally, RNA binding protein NOVA2 was shown to regulate splicing of FLT1 mRNA. Loss of NOVA2 resulted in an increase in the soluble variant of FLT1. We also observed endothelial dysfunction after loss of NOVA2. We further investigated a potential role for NOVA2 in the pathophysiology of pre-eclampsia. In conclusion, this thesis contributes to a better understanding of the regulation of endothelial function, specifically the regulation of the barrier and angiogenic sprouting.