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.
Highlights
Genetic studies have demonstrated the importance of nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling in cardiovascular health and disease in humans[9,10], the underlying cellular and molecular mechanisms are not completely understood
It is long known that platelets express high levels of NO sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase I, and that the intraplatelet cGMP concentration can be increased in vitro by incubation with NO, or with drugs that stimulate NO-GC or inhibit cGMP degradation by phosphodiesterases (PDEs)[11,12,13]
While it is well established that the NO-cGMP pathway is a major mechanism for platelet inhibition, it is increasingly recognized that this pathway may play a biphasic role in both platelet activation and inhibition
Summary
Genetic studies have demonstrated the importance of NO-cGMP signaling in cardiovascular health and disease in humans[9,10], the underlying cellular and molecular mechanisms are not completely understood. While it is well established that the NO-cGMP pathway is a major mechanism for platelet inhibition, it is increasingly recognized that this pathway may play a biphasic role in both platelet activation and inhibition. An increase in platelet cGMP has been linked to platelet activation induced by several receptor signaling pathways, including recently discovered platelet pattern-recognition receptor signaling pathways that are triggered by damageassociated molecular pattern molecules such as high mobility group box 1 protein[17]. To study the role of flow/shear stress for NOcGMP signaling in platelets, we have generated cGMP sensor mice that enable real-time visualization of cGMP signals during thrombus formation. We find that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent both in a flow chamber assay as well as in two mouse models of arterial injury and thrombosis. The mechanosensitive NO-cGMP-cGKI pathway identified in this study acts as an auto-regulatory brake to prevent vessel occlusion under high shear, while preserving wound closure under low shear
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