Factor Seven Activating Protease (FSAP) is a circulating protease with a rolein coagulation, fibrinolysis and inflammation. The FSAP-Marburg I polymorphism,with low proteolytic activity, is associated with an increased risk of stroke and late complications of carotid stenosis in humans. We recently showed that FSAP antigen and activity levels are elevated in patients with Ischemic Stroke. In order to find a mechanistic explanation for this we have investigated the effect of FSAP on primary mouse brain microvascular endothelial cells, astrocytes and neurons. We demonstrate that FSAP can regulate endothelial permeability in an in-vitro model of the blood brain barrier (BBB) by stabilizing junctional localization of ZO-1 and by preventing the opening of the endothelial tight junctions after oxygen glucose deprivation (OGD)/reoxygenation. Furthermore, FSAP can cross the BBB and exert a protectiveeffect on cortical astrocytes and neurons exposed to conditions mimicking stroke by activating the PI3K-Akt pathway. This protective effect was mediated by PAR-1 dependent activation of Akt pathway and dependent on its proteolytic activity. In a mouse in-situ thromboembolic stroke model, we observed that infarction volumes at 24 hours were significantly larger in FSAP-/- mice and neurological score worse. However, no difference was observed in the either cerebral reperfusion or cerebral vasculature. Increased FSAP antigen and activity levels were detected in WT mice after stroke in accordance with the clinical findings. In the absence of endogenous FSAP, there was a tendency towards a pro-inflammatory phenotype post stroke. Also, the lack of FSAP after stroke resulted in decreased Akt phosphorylation and Bcl-2 levels while increased levels of p53 were observed. Thus, from the data presented in this thesis, we propose that FSAP is a novel neuroprotective agent of the neurovascular unit and loss of FSAP activity could suggest the possible mechanism which leads to less protection in Marburg I polymorphism patients.
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