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. 2024 Dec;35(1):2313359.
doi: 10.1080/09537104.2024.2313359. Epub 2024 Feb 14.

Role of the NO-GC/cGMP signaling pathway in platelet biomechanics

Aylin Balmes  1 , Johanna G Rodríguez  1   2 , Jan Seifert  1 , Daniel Pinto-Quintero  3 , Akif A Khawaja  2 , Marta Boffito  4   5 , Maike Frye  6 , Andreas Friebe  7 , Michael Emerson  2 , Francesca Seta  8 , Robert Feil  3 , Susanne Feil  3 , Tilman E Schäffer  1
Affiliations

Role of the NO-GC/cGMP signaling pathway in platelet biomechanics

Aylin Balmes et al. Platelets. 2024 Dec.

Abstract

Cyclic guanosine monophosphate (cGMP) is a second messenger produced by the NO-sensitive guanylyl cyclase (NO-GC). The NO-GC/cGMP pathway in platelets has been extensively studied. However, its role in regulating the biomechanical properties of platelets has not yet been addressed and remains unknown. We therefore investigated the stiffness of living platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat using scanning ion conductance microscopy (SICM). Stimulation of human and murine platelets with cGMP-modulating drugs decreased cellular stiffness and downregulated P-selectin, a marker for platelet activation. We also quantified changes in platelet shape using deep learning-based platelet morphometry, finding that platelets become more circular upon treatment with cGMP-modulating drugs. To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulfate (ABC)-containing regimens. Our results corroborate a functional role of the NO-GC/cGMP pathway in platelet biomechanics, indicating that biomechanical properties such as stiffness or shape could be used as novel biomarkers in clinical research.

Keywords: Cellular stiffness; NO-sensitive guanylyl cyclase (NO-GC) enzyme; cyclic guanosine monophosphate (cGMP); inhibition of platelet activation; platelet shape.

Plain language summary

Increased platelet activation and development of thrombosis has been linked to a dysfunctional NO-GC/cGMP signaling pathway. How this pathway affects platelet stiffness, however, has not been studied yet. For the first time, we used novel microscopy techniques to investigate stiffness and shape of platelets in human and murine blood samples treated with cGMP modifying drugs. Stiffness contains information about biomechanical properties of the cytoskeleton, and shape quantifies the spreading behavior of platelets. We showed that the NO-GC/cGMP signaling pathway affects platelet stiffness, shape, and activation in human and murine blood. HIV-positive patients are often treated with medication that may disrupt the NO-GC/cGMP signaling pathway, leading to increased cardiovascular risk. We showed that treatment with cGMP-modifying drugs altered platelet shape and aggregation in blood from HIV-negative volunteers but not from HIV-positive patients treated with medication. Our study suggests that platelet stiffness and shape can be biomarkers for estimating cardiovascular risk.

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