A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis
Date
2018-10-16
Authors
Wen, Lai
Feil, Susanne
Wolters, Markus
Thunemann, Martin
Regler, Frank
Schmidt, Kjestine
Friebe, Andreas
Olbrich, Marcus
Langer, Harald
Gawaz, Meinrad
Version
Published version
OA Version
Citation
Lai Wen, Susanne Feil, Markus Wolters, Martin Thunemann, Frank Regler, Kjestine Schmidt, Andreas Friebe, Marcus Olbrich, Harald Langer, Meinrad Gawaz, Cor de Wit, Robert Feil. 2018. "A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis.." Nat Commun, Volume 9, Issue 1, pp. 4301 - ?. https://doi.org/10.1038/s41467-018-06638-8
Abstract
Mechanisms that limit thrombosis are poorly defined. One of the few known endogenous platelet inhibitors is nitric oxide (NO). NO activates NO sensitive guanylyl cyclase (NO-GC) in platelets, resulting in an increase of cyclic guanosine monophosphate (cGMP). Here we show, using cGMP sensor mice to study spatiotemporal dynamics of platelet cGMP, that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent. We delineate a new mode of platelet-inhibitory mechanotransduction via shear-activated NO-GC followed by cGMP synthesis, activation of cGMP-dependent protein kinase I (cGKI), and suppression of Ca2+ signaling. Correlative profiling of cGMP dynamics and thrombus formation in vivo indicates that high cGMP concentrations in shear-exposed platelets at the thrombus periphery limit thrombosis, primarily through facilitation of thrombus dissolution. We propose that an increase in shear stress during thrombus growth activates the NO-cGMP-cGKI pathway, which acts as an auto-regulatory brake to prevent vessel occlusion, while preserving wound closure under low shear.
Description
License
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