Understanding the mechanisms by which pathogens induce vascular inflammation and 
dysfunction may reveal novel therapeutic targets in sepsis and related 
conditions. The intracellular receptor NOD1 recognises peptidoglycan which 
features in the cell wall of gram negative and some gram positive bacteria. NOD1 
engagement generates an inflammatory response via activation of NFκB and MAPK 
pathways. We have previously shown that stimulation of NOD1 directly activates 
blood vessels and causes experimental shock in vivo. In this study we have used 
an ex vivo vessel-organ culture model to characterise the relative contribution 
of the endothelium in the response of blood vessels to NOD1 agonists. In 
addition we present the novel finding that NOD1 directly activates human blood 
vessels. Using human cultured cells we confirm that endothelial cells respond 
more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we 
have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling 
pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In 
addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically 
inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This 
paper is the first to demonstrate activation of whole human artery by NOD1 
stimulation and the relative importance of the endothelium in the sensing of 
NOD1 ligands by vessels. This data supports the potential utility of NOD1 and 
RIP2 as therapeutic targets in human disease where vascular inflammation is a 
clinical feature, such as in sepsis and septic shock.