Local ubiquitylation contrals vascular integrity and inflammation. (LSBR 1311)
Prof. Dr. Peter L. Hordijk, Sanquin Research, Dept. Molecular Cell Biology (Aug. 2014 – Dec. 2015), VUmc Dept. of Physiology (Jan. 2016 – July 2017)
Postdoc investigator: I. Kovacevic (100% Aug. 2014 – Aug 2017, Sanquin and VUmc)
Research technician: Eloise Anthony (89% Aug. 2014 – Jun 2016, Sanquin))
Research technician: Jan van Bezu (89% Febr. 2016 – July 2017 ,VUmc)
An important aspect of our blood vessels is their permeability. This permeability allows for efficient exchange of nutrients and waste between blood and tissues as well as for extravasation of leukocytes to sites of acute or chronic inflammation. Our blood vessels are lined, on the inside, by a continuous monolayer of endothelial cells, the intercellular contacts of which determine blood vessel permeability. This differs between different tissues but changes also in disease: in particular inflammation increases vascular permeability, which may lead to: (i) tissue damage by extravasated leukocytes, (ii) oedema and (iii) amplification of the inflammation. Thus, it is imperative to have a good understanding of the modes of regulation of endothelial and thus of blood vessel permeability.
This project has focused on a mechanism that was not studied previously and that controls endothelial permeability. We found that a specific regulatory protein, RhoB, negatively controls the intercellular contacts between endothelial cells: when RhoB is activated, endothelial cells contract and dissociate partially from each other, causing leakage. In endothelial cells, RhoB is continuously synthesized but also rapidly degraded. This renders our endothelium usually ‘closed’. The degradation of RhoB is relevant for this effect, but was mechanistically poorly understood. We have now discovered which enzyme controls the degradation of RhoB. This is relevant, since it may allow use of activators or inhibitors of this enzyme in order to control vascular leakage. This, in turn, could lead to reduction or inhibition of inflammatory reactions. This research was recently submitted for publication.
In parallel, we performed a number of sub-projects that were all related to this topic. For example, we studied the degradation of Rac1, a protein that stabilizes endothelial barrier function and prevents leakage. Rac1 thus counteracts RhoB. We are specifically interested in the balance between these two pathways in vascular stability. This line of research is currently being pursued in our department, as a continuation of this LSBR project.
Finally, in addition to these more fundamental studies, we also started a translational sub-project by testing to what extent plasma samples from patients suffering from pre-eclampsia (associated with inflammation, oedema and hypertension), could alter the permeability of otherwise healthy endothelial cells. We found indeed that plasma from such patients can increase endothelial permeability, with a strong correlation with obesity. The results from this work have recently been submitted for publication.
These research lines will be continued within our department and in collaboration with the AMC.