A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Wen, Lai; Feil, Susanne; Wolters, Markus; Thunemann, Martin; Regler, Frank; Schmidt, Kjestine; Friebe, Andreas; Olbrich, Marcus; Langer, Harald; Gawaz, Meinrad; Wit, Cor; Feil, Robert
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 11
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06638-8
• Languages: English
• ISSNs: 2041-1723

Abstract

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. Nitric oxide (NO) inhibits thrombosis in part by stimulating cyclic guanosine monophosphate (cGMP) production and cGMP-dependent protein kinase I (cGKI) activity in platelets. Here, Wen et al. develop a cGMP sensor mouse to follow cGMP dynamics in platelets, and find that shear stress activates NO-cGMP-cGKI signaling during platelet aggregation to limit thrombosis.