Platelet-localized FXI promotes a vascular coagulationinflammatory circuit in arterial hypertension

Sabine Kossmann, Jeremy Lagrange, Sven Jäckel, Kerstin Jurk, Moritz Ehlken, Tanja Schönfelder, Yvonne Weihert, Maike Knorr, Moritz Brandt, Ning Xia, Huige Li, Andreas Daiber, Matthias Oelze, Christoph Reinhardt, Karl Lackner, Andras Gruber, Brett Monia, Susanne H. Karbach, Ulrich Walter, Zaverio M. Ruggeri & 4 others Thomas Renné, Wolfram Ruf, Thomas Münzel, Philip Wenzel

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function. In mice with angiotensin II-induced hypertension, tissue factor was up-regulated, as was thrombin-dependent endothelial cell vascular cellular adhesion molecule 1 expression and integrin αMβ2-And platelet-dependent leukocyte adhesion to arterial vessels. The resulting vascular inflammation and dysfunction was mediated by activation of thrombin-driven factor XI (FXI) feedback, independent of factor XII. The FXI receptor glycoprotein Iba on platelets was required for this thrombin feedback activation in angiotensin II-infused mice. Inhibition of FXI synthesis with an antisense oligonucleotide was sufficient to prevent thrombin propagation on platelets, vascular leukocyte infiltration, angiotensin II-induced endothelial dysfunction, and arterial hypertension in mice and rats. Antisense oligonucleotide against FXI also reduced the increased blood pressure and attenuated vascular and kidney dysfunction in rats with established arterial hypertension. Further, platelet-localized thrombin generation was amplified in an FXI-dependent manner in patients with uncontrolled arterial hypertension, suggesting that platelet-localized thrombin generation may serve as an inflammatory marker of high blood pressure. Our results outline a coagulation-inflammation circuit that promotes vascular dysfunction, and highlight the possible utility of FXI-Targeted anticoagulants in treating hypertension, beyond their application as antithrombotic agents in cardiovascular disease.

Original languageEnglish (US)
Article numbereaah4923
JournalScience Translational Medicine
Volume9
Issue number375
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

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Factor XI
Blood Vessels
Blood Platelets
Hypertension
Thrombin
Angiotensin II
Leukocytes
Antisense Oligonucleotides
Factor XII
Blood Pressure
Inflammation
Fibrinolytic Agents
Vascular Cell Adhesion Molecule-1
Thromboplastin
Integrins
Venous Thrombosis
Anticoagulants
Reactive Oxygen Species
Glycoproteins
Cardiovascular Diseases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kossmann, S., Lagrange, J., Jäckel, S., Jurk, K., Ehlken, M., Schönfelder, T., ... Wenzel, P. (2017). Platelet-localized FXI promotes a vascular coagulationinflammatory circuit in arterial hypertension. Science Translational Medicine, 9(375), [eaah4923]. https://doi.org/10.1126/scitranslmed.aah4923

Platelet-localized FXI promotes a vascular coagulationinflammatory circuit in arterial hypertension. / Kossmann, Sabine; Lagrange, Jeremy; Jäckel, Sven; Jurk, Kerstin; Ehlken, Moritz; Schönfelder, Tanja; Weihert, Yvonne; Knorr, Maike; Brandt, Moritz; Xia, Ning; Li, Huige; Daiber, Andreas; Oelze, Matthias; Reinhardt, Christoph; Lackner, Karl; Gruber, Andras; Monia, Brett; Karbach, Susanne H.; Walter, Ulrich; Ruggeri, Zaverio M.; Renné, Thomas; Ruf, Wolfram; Münzel, Thomas; Wenzel, Philip.

In: Science Translational Medicine, Vol. 9, No. 375, eaah4923, 01.02.2017.

Research output: Contribution to journalArticle

Kossmann, S, Lagrange, J, Jäckel, S, Jurk, K, Ehlken, M, Schönfelder, T, Weihert, Y, Knorr, M, Brandt, M, Xia, N, Li, H, Daiber, A, Oelze, M, Reinhardt, C, Lackner, K, Gruber, A, Monia, B, Karbach, SH, Walter, U, Ruggeri, ZM, Renné, T, Ruf, W, Münzel, T & Wenzel, P 2017, 'Platelet-localized FXI promotes a vascular coagulationinflammatory circuit in arterial hypertension', Science Translational Medicine, vol. 9, no. 375, eaah4923. https://doi.org/10.1126/scitranslmed.aah4923
Kossmann, Sabine ; Lagrange, Jeremy ; Jäckel, Sven ; Jurk, Kerstin ; Ehlken, Moritz ; Schönfelder, Tanja ; Weihert, Yvonne ; Knorr, Maike ; Brandt, Moritz ; Xia, Ning ; Li, Huige ; Daiber, Andreas ; Oelze, Matthias ; Reinhardt, Christoph ; Lackner, Karl ; Gruber, Andras ; Monia, Brett ; Karbach, Susanne H. ; Walter, Ulrich ; Ruggeri, Zaverio M. ; Renné, Thomas ; Ruf, Wolfram ; Münzel, Thomas ; Wenzel, Philip. / Platelet-localized FXI promotes a vascular coagulationinflammatory circuit in arterial hypertension. In: Science Translational Medicine. 2017 ; Vol. 9, No. 375.
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AU - Ehlken, Moritz

AU - Schönfelder, Tanja

AU - Weihert, Yvonne

AU - Knorr, Maike

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AU - Li, Huige

AU - Daiber, Andreas

AU - Oelze, Matthias

AU - Reinhardt, Christoph

AU - Lackner, Karl

AU - Gruber, Andras

AU - Monia, Brett

AU - Karbach, Susanne H.

AU - Walter, Ulrich

AU - Ruggeri, Zaverio M.

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