Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension
S. Kossmann1, J. Lagrange1, S. Jackel1, K. Jurk1, M. Ehlken1, A. Daiber1, U. Walter1, T. Renné2,3, W. Ruf1,4, T. Munzel1, P. Wenzel1 (1Mainz, Germany, 2Hamburg, Germany, 3Stickholm, Schweden, 4La Jolla, USA)
Vascular wall biology and disorders
Time: 17:15 - 18:15
Objective: High levels of angiotensin II (ATII) cause hypertension by a complex inflammatory pathway requiring leukocyte recruitment and reactive oxygen species production within the vessel wall coupled to vascular dysfunction. The aim of this work was to explore the role of thrombin FXI feedback loop in animal models of arterial hypertension.
Methods: To induce hypertension mice on a C57BL/6 background were infused with ATII (s.c. 1 mg/kg/d for 7d) and Wistar rats underwent 5/6 nephrectomy (Nx).
Results: Here we report an upregulation of tissue factor, thrombin dependent vascular VCAM1 expression and platelet dependent leukocyte adhesion to arterial vessels in ATII-infused mice. ATII-induced vascular dysfunction and Ccl2, VCAM1 and Ly6C mRNA expression were attenuated by thrombin inhibition, platelet depletion as well as in hIL4R/Ibalpha mice missing the extracellular ligand binding domains of GPIbalpha. Blockade of TF during ATII administration also attenuated vascular dysfunction and reduced vascular oxidative stress. PRP of ATII-treated mice showed an increased thrombin evoked endogenous thrombin potential (ETP), whereas PRP from mice with pharmacological inhibition of FXI production by an FXI antisense oligonucleotide (FXI ASO) or PRP of hIL4R/Ibalpha mice failed to amplify ETP following ATII exposure. These data show that a FXI-dependent thrombin generation feedback loop requires GPIbalpha on platelets and suggest that TF-initiated coagulation promotes additional thrombin formation on platelets to cause vascular inflammation. To further evaluate the therapeutic potential of interrupting FXI synthesis and function on blood pressure we used an additional hypertension model. Nx rats were either preventively injected with FXI ASO or injection was started when blood pressure was already significantly upregulated. Nx rats revealed endothelial dysfunction, vascular oxidative stress, kidney damage as well as an increase in blood pressure. FXI ASO injection in a preventive way or as a treatment significantly improved vascular and renal injury and persistently reduced arterial hypertension.
Conclusion: These novel benefits of FXI inhibitors might add to their applicability as antithrombotic agents, especially in cardiovascular disease with an activated RAAS.