A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis
Please always quote using this URN: urn:nbn:de:bvb:20-opus-233616
- 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 cGMPMechanisms 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.…
Author: | 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 |
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URN: | urn:nbn:de:bvb:20-opus-233616 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Physiologisches Institut |
Language: | English |
Parent Title (English): | Nature Communications |
Year of Completion: | 2018 |
Volume: | 9 |
Article Number: | 4301 |
Source: | Nature Communications (2018) 9:4301. https://doi.org/10.1038/s41467-018-06638-8 |
DOI: | https://doi.org/10.1038/s41467-018-06638-8 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | calcium signalling; fluorescence imaging; platelets; thrombosis |
Release Date: | 2024/07/18 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |