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.