Signaling in vascular biology: The role of GTPases and GEFs in endothelial cell function

In this thesis we describe several important aspects of vascular biology. We studied how long-term blood flow influences endothelial cell function and demonstrated that the Rho-GEF Trio is one of the key molecules important in long-term adaptation of endothelial cells. In a follow-up study we furthermore identified an important role for this protein in sprouting angiogenesis, i.e. the formation of novel blood vessels out of existing ones. In addition, we assessed the role of the GTPase RhoB under inflammatory conditions, e.g. downstream of TNFα, an important inflammatory mediator and describe a robust method how to visualize leukocyte transendothelial migration under physiological flow conditions.
Using this method, we found an important role for microvilli-like structures called filopodia on the apical side of the endothelium that are required for efficient transendothelial migration of leukocytes. Moreover, we identified an important role for the Rho-GEF Trio downstream of the adhesion molecule ICAM-1, being a crucial component involved in efficient leukocyte capturing and transmigration. Finally, we showed that uncontrolled leukocyte extravasation can lead to the development of atherosclerosis.