2. Academic Validation
  3. A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis

A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis

  • Nat Commun. 2018 Oct 16;9(1):4301. doi: 10.1038/s41467-018-06638-8.
Lai Wen 1 2,  Susanne Feil 1,  Markus Wolters 1,  Martin Thunemann 1,  Frank Regler 1,  Kjestine Schmidt 3,  Andreas Friebe 4,  Marcus Olbrich 5,  Harald Langer 5,  Meinrad Gawaz 5,  Cor de Wit 3,  Robert Feil 6
Affiliations

Affiliations

  • 1 Interfakultäres Institut für Biochemie, University of Tübingen, 72076, Tübingen, Germany.
  • 2 Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, CA, USA.
  • 3 Institut für Physiologie, Universität zu Lübeck, 23562 Lübeck, Germany.
  • 4 Physiologisches Institut, University of Würzburg, 97070 Würzburg, Germany.
  • 5 University Hospital, Department of Cardiology and Cardiovascular Medicine, University of Tübingen, 72076 Tübingen, Germany.
  • 6 Interfakultäres Institut für Biochemie, University of Tübingen, 72076, Tübingen, Germany. [email protected].
PMID: 30327468 DOI: 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.

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