Coagulation FACTors and platelet GlycoProtein Ib alpha: A thrombo-inflammatory hub inVASCular dysfunction and disease (FACT-GP VASC)

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There is a gap in evidence, how the combined inflammatory actions of coagulation factors and platelets modulate cardiovascular disease. In prior work we could demonstrate a physiological role of the FIIa-FXI fedback activation loop involving platelet glycoprotein Ib alpha (GPIbα) in the vascular disease of arterial hypertension, interestingly in the absence of clotting. In FACT-GP VASC, I will disentangle the interaction of von Willebrand Factor (vWF), FXI, FIIa and GPIbα in vascular inflammation. Using genetically engineered mice that either lack vWF or FIIa binding to the GPIbα as well as innovative intravital imaging techniques and thrombin generation assays, I will unravel what is afforded to permit the FIIa-FXI feedback amplification loop, which is necessary to propel vascular inflammation (Aim I). Making use of antisense oligonucleotide depletion techniques, I will define the roles of pre-kallikrein and kininogen to dissect converging or synergistic pathways that could mediate the vascular protective effects of FXI inhibition. I will next translate concept and techniques to the chronic myocardial infarction model, characterized by angiotensin II-dependent vascular inflammation. Thereby I aim to prove that particular ligand-properties of GPIbα convey vascular protection in the absence of perturbed wound healing or bleeding (Aim II). My research therefore enters new and largely uncharted scientific territories. I aim to establish GPIbα as a hitherto unclaimed druggable target in vascular inflammation beyond haemostasis. My results could have a major impact for people suffering from cardiovascular disease, the leading cause for morbidity and mortality worldwide.