Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension.
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 Ibα 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.
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.|Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Sabine
S
Kossmann
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Jeremy
J
Lagrange
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Sven
S
Jäckel
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Kerstin
K
Jurk
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.|Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Moritz
M
Ehlken
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Tanja
T
Schönfelder
Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Yvonne
Y
Weihert
Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Maike
M
Knorr
Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Moritz
M
Brandt
Department of Pharmacology, University Medical Center Mainz, 55131 Mainz, Germany.
Ning
N
Xia
Department of Pharmacology, University Medical Center Mainz, 55131 Mainz, Germany.
Huige
H
Li
Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Andreas
A
Daiber
Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Matthias
M
Oelze
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Christoph
C
Reinhardt
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, 55131 Mainz, Germany.
Karl
K
Lackner
Department of Biomedical Engineering, Oregon Health and Science University, 3303 Southwest Bond Avenue, CH13B, Portland, OR 97239, USA.|Aronora Inc., 4640 Southwest Macadam Avenue, Suite 200A, Portland, OR 97239, USA.
Andras
A
Gruber
Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Brett
B
Monia
Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.
Susanne H
SH
Karbach
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Ulrich
U
Walter
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Zaverio M
ZM
Ruggeri
Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet, SE-171 71 Stockholm, Sweden.|Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Thomas
T
Renné
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.|DZHK (German Center for Cardiovascular Research), Partner Site Rhine Main, University Medical Center Mainz, 55131 Mainz, Germany.
Wolfram
W
Ruf
Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Rhine Main, University Medical Center Mainz, 55131 Mainz, Germany.
Thomas
T
Münzel
Center for Thrombosis and Hemostasis Mainz, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. wenzelp@uni-mainz.de.|Center for Cardiology, Cardiology I, University Medical Center Mainz, 55131 Mainz, Germany.|DZHK (German Center for Cardiovascular Research), Partner Site Rhine Main, University Medical Center Mainz, 55131 Mainz, Germany.
Philip
P
Wenzel
D000368:Aged; D000804:Angiotensin II; D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000166:cytology*; D001794:Blood Pressure; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D017208:Rats, Wistar; D013917:Thrombin / Q000502:physiology*; D013925:Thromboplastin / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D016177:Macrophage-1 Antigen; D016376:Oligonucleotides, Antisense; D019038:Platelet Glycoprotein GPIb-IX Complex; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D005172:Factor XI; D013925:Thromboplastin; D013917:Thrombin