P1.9 PLATELET-LOCALIZED FXI PROMOTES A GLYCOPROTEIN IBα DEPENDENT FEEDBACK LOOP IN ARTERIAL HYPERTENSION AND VASCULAR INFLAMMATION
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Background: Interactions of platelets, leukocytes and the vessel wall play pivotal roles in activating coagulation and precipitating thrombosis. High levels of angiotensin II (ATII) cause arterial hypertension by a complex inflammatory pathway requiring leukocyte recruitment and reactive oxygen species production within the vessel wall.
Objective: The aim of this work was to explore the role of platelet glycoprotein Ibα dependent thrombin-FXI feedback loop in arterial hypertension.
Methods: FXII−/−, FXI−/−, and hIL-4R/Ibα mice and 5/6 nephrectomized rats were used for this study. Mice where treated with ATII (1mg/kg−1/d−1 for 7 days) using osmotic minipumps. Blood pressure was recorded using tail cuff measurement and telemetry carotid implants. Vascular reactivity was assessed in isolated aortic segment, and thrombin generation was measured using calibrated automated thrombography.
Results: ATII induces an upregulation of tissue factor, thrombin-dependent endothelial cell VCAM-1 expression and integrin α4- and platelet-dependent leukocyte adhesion to arterial conductance vessels. The resulting vascular dysfunction unexpectedly involved the activation of FXI but not FXII. The platelet FXI receptor glycoprotein Ibα supports the upregulation of thrombin feedback activation in ATII-treated mice. Importantly, pharmacologic inhibition of FXI synthesis is sufficient to prevent thrombin propagation on platelets, to reduce vessel wall leukocyte infiltration, and to diminish ATII-induced endothelial dysfunction and arterial hypertension in mice and rats.
Conclusion: Our results reveal a critical role of platelet GPIbα to promote localized thrombin amplification and a FXI-thrombin feedback loop in ATII-induced vascular inflammation. Targeting FXI could be a novel therapeutic possibility to interrupt this heterotypic cellular coagulation-inflammatory circuit.
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TY - JOUR AU - Jeremy Lagrange* AU - Sabine Kossmann AU - Moritz Ehlken AU - Brett Monia AU - Wolfram Ruf AU - Philip Wenzel PY - 2015 DA - 2015/11 TI - P1.9 PLATELET-LOCALIZED FXI PROMOTES A GLYCOPROTEIN IBα DEPENDENT FEEDBACK LOOP IN ARTERIAL HYPERTENSION AND VASCULAR INFLAMMATION JO - Artery Research SP - 4 EP - 5 VL - 12 IS - C SN - 1876-4401 UR - https://doi.org/10.1016/j.artres.2015.10.201 DO - https://doi.org/10.1016/j.artres.2015.10.201 ID - Lagrange*2015 ER -