RESUMEN
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.
Asunto(s)
Plaquetas/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , GMP Cíclico/metabolismo , Óxido Nítrico/metabolismo , Trombosis/metabolismo , Animales , Calcio/metabolismo , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/genética , Transferencia Resonante de Energía de Fluorescencia , Humanos , Ratones Transgénicos , Activación Plaquetaria , Transducción de Señal , Estrés Mecánico , Trombosis/fisiopatologíaRESUMEN
The original version of this Article contained an error in the description of Supplementary Movie 4, in which the final sentence was inadvertently truncated. The HTML has been updated to include a corrected version of the 'Description of Additional Supplementary Files' file.