Protecting the endothelium: Post-transcriptional control of barrier function by Quaking

All blood vessels are lined with a single layer of endothelial cells (ECs), which form a vital barrier between the blood and underlying tissue. The control of the EC barrier is critical to maintain vascular stability and retain circulating fluids, solutes, proteins and cells within the vasculature. Excessive vascular permeability plays a key role in many pathophysiological conditions such as septic shock, vascular leakage, hypertension, edema and atherosclerosis. Inter-endothelial contacts within the monolayer must therefore be maintained for proper barrier function, while on the other hand, the cellular junctions must be sufficiently plastic to allow the growth and development of blood vessels, as well as the passage of leukocytes to the underlying tissue in case of an inflammatory reaction.These specialized endothelial cell-cell adhesions are mediated by adherens, tight- and gap junctions. In ECs, cell-cell interactions at adherens junctions are facilitated by the transmembrane protein VE-cadherin, of which the extracellular domain forms a zipper-like structure between the cells. The intracellular domain of VE-cadherin is linked to the actin cytoskeleton via a complex array of structural and signaling proteins, including β-, γ-, α- and p120-catenins.

In recent years, the importance of post-transcriptional control of gene expression in EC biology has become increasingly evident. Upon commencing with my post-doctoral studies in the laboratory of Prof. Erik Biessen, I undertook immunohistochemical for Quaking in the healthy artery wall. These studies revealed that Quaking was virtually absent in VSMCs, but abundantly expressed in the healthy endothelium. This observation sparked intensive investigation of the role of Quaking in ECs in healthy and diseased arteries. This work culminated in our recent publication that details mechanistically how QKI functions as a novel post-transcriptional regulator of VE-cadherin and β-catenin. By directly regulating the expression of these critical barrier function-maintaining proteins, QKI strengthens its position as a pivotal regulator of EC function in health and disease.

Our ongoing studies into Quaking and ECs therefore is focusing on the role of this protein in guiding post-transcriptional processes in both the macro- and microvascular setting.