Interplay between co-stimulatory signalling and extracellular matrix in atherosclerotic plaque stabilization

BACKGROUND

The main underlying cause of cardiovascular disease (CVD) is atherosclerosis: inflamed plaques in the blood vessels that can cause stroke or myocardial infarction upon rupture. Extracellular matrix (ECM) integrity is of crucial importance for the development and stability of atherosclerotic plaques. Understanding of how immune responses control ECM turnover is currently lacking but is of utmost importance to control the disease process. One potential link between inflammation and the ECM milieu is the co-stimulatory molecules.

AIMS

My hypothesis is that the co-stimulatory LIGHT/HVEM dyad has an instrumental role in interactions between SMCs and the plaque ECM microenvironment and drives atherosclerosis progression and plaque destabilization. This proposal will define how atherosclerotic plaque development is driven by effects of these co-stimulatory molecules on and by ECM integrity and turnover through investigating:

1. how soluble LIGHT in plasma is associated with CVD in humans 2. how HVEM-triggering drives SMC behaviour in an inflammatory micro-environment 3. how HVEM-triggering drives SMC fibrous response and phenotypic modulation 4. LIGHT/HVEM-expression in early compared to advanced plaque development WORK PLAN

Human carotid endarterectomy plaques and plasma from individuals with and without CVD will be analysed for associations between LIGHT/HVEM levels, plaque vulnerability markers and prevalent CVD. LIGHT/HVEM triggering will be further explored in vitro in SMC primary culture 2D- and 3D-systems, where effects on the SMC fibrous response (collagen synthesis in particular) and phenotype modulation are mapped.

Finally, a mouse model of atherosclerosis will be used to determine whether LIGHT/HVEM triggering is most prominent in initial or advanced plaque development. SIGNIFICANCE

Interventions in the immune system, and especially in co-stimulatory pathways, are potent novel strategies for treatment of atherosclerosis in a laboratory setting, as they can affect inflammation without leading to damaging immunosuppressive side effects. Identifying a direct role for LIGHT/HVEM signalling in atherosclerotic plaque ECM turnover – and thus stability – will provide further understanding of how inflammation is mediated in an atherosclerotic plaque environment with the ultimate goal to identify novel drug targets.