Broken symmetry and novel molecular players in endothelial adherens junctions

The endothelium is the layer of endothelial cells covering the inside of the blood vessels. The endothelium serves as a selectively permeable barrier which allows controlled passage of cells, particles and solutes from the blood to the tissues. Perturbation in the endothelial barrier function causes constituents of the blood to leak uncontrolled into the vessel’s surroundings leading to edema and inflammation. This aberrant leakage is a condition known as vascular hyperpermeability which occurs with age, exacerbates cardiovascular diseases, promotes tumor growth and is the main cause of sepsis. It is thus of clinical importance to understand in depth the molecular mechanisms which control the vascular barrier and this is the focus of the current thesis.
The integrity of the endothelial barrier is defined mainly by the tightness of the contacts between the endothelial cells. These contacts named adherens junctions (AJs) are based on the transmembrane protein Vascular Endothelial-cadherin (VE-cadherin). This doctoral thesis explores new VE-cadherin interactors at the endothelial AJs and studies their role in the control of vascular homeostasis. Through the methods of advanced imaging, biochemistry, mass spectrometry and knockout mouse models the thesis sheds light on novel AJs related proteins and molecular events which control the stability of VE-cadherin at the endothelial cell membrane. Finally, the thesis applies these novel findings to understand better the mechanism of action of novel nanoparticle-based atherosclerosis therapies. In conclusion, this doctoral thesis contains original innovative research which contributes to the area of endothelial AJs and cardiovascular medicine.