CCBIO seminar: Guttorm Haraldsen
Vascular endothelial cells in quiescence and activation
K.G. Jebsen Inflammation Research Centre, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo
Vascular endothelial cells are central players in the initiation and amplification of inflammatory responses, and their role in recruiting leukocytes to inflammatory lesions is now well characterized. Likewise, we have a good understanding of the signals and receptor systems that induce vascular sprouting and angiogenesis. By contrast, we are only beginning to understand the mechanisms that control their general responsiveness to proinflammatory or proangiogenic mediators. Recent studies illustrate that gaining control over this vascular responsiveness may confer great benefits to human health.
Our lab has focused on understanding mechanisms related to vascular quiescence and the role of the Notch signalling system. Indeed, it appears that the Notch ligand Dll4 is crucially involved in the induction of vascular quiescence. Moreover, we have discovered that inhibition of the Notch ligand Jagged1 or the receptor Notch1 in endothelial cells impaired their inflammatory response to IL-1β, including reduced expression of adhesion molecules, chemokines and the chemokine transcytosis receptor DARC. Furthermore, endothelial cell-targeted, inducible knockout of the canonical Notch transcription factor RBPJ/CSL reduced inflammation in a mouse model of contact dermatitis. Conversely, transgenic overexpression of active Notch1 in endothelial cells enhanced the inflammatory response. In conclusion, we show for the first time that Notch signalling modulates gene expression in activated endothelial cells, sharpening the inflammatory profile of the vasculature and giving it an edge towards leukocyte recruitment.
Chairperson: Lars A. Akslen, CCBIO