The role of the YAP signalling pathway in mechanisms of blood-brain barrier dysfunction and remodelling after stroke

The extracellular matrix (ECM) of the central nervous system (CNS) provides a structural and functional environment for the cells of the neurovascular unit that is essential for maintenance of blood-brain barrier (BBB) integrity and brain functions. However, after stroke, the BBB undergoes profound changes associated with the breakdown of tight junctions, remodelling of the ECM and enzymatic degradation of ECM proteins. The cytokine interleukin(IL)-1 is an established mediator of the pro-inflammatory response associated with BBB dysfunction and subsequent tissue damage. Although IL-1 is known to exert detrimental actions during the acute phase of stroke, increasing evidence suggests a biphasic action of IL-1 that exhibits neuroreparative properties during the sub-acute phase after stroke. Furthermore, ECM remodelling after CNS injury is associated with BBB repair, and IL-1 has been shown to mediate repair mechanisms, leading to the hypothesis that BBB repair driven by IL-1 could be regulated by ECM remodelling. Indeed, we have recently demonstrated laminin-10 (LM-10) as a key ECM molecule involved in BBB repair after hypoxic injury and IL-1B-induced inflammation in vitro. The YAP/Hippo pathway has recently gained significant interest as an extremely dynamic pathway implicated in ECM remodelling, and it is well established that ECM-integrin signalling is a key step in the initiation of the YAP pathway. Critically, we have recently demonstrated that IL-1B and LM-10 regulated YAP signalling pathway in endothelial cells leading to differential expression of YAP target genes and hallmarks of angiogenesis. However the in vivo relevant of those findings on stroke outcome and recovery and the potential targeting of the YAP signalling pathway in stroke is completely unknown. The aim of this project is therefore to further investigate the role of the YAP signalling pathway during ECM remodelling and inflammation on BBB dysfunction and repair in vitro, and to test the in vivo relevance that targeting the ECM / YAP signalling pathway axis can be exploited for functional recovery after stroke.