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
  • 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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