Institute of Applied Physics, University of Tübingen, Tübingen, Germany.
National Heart and Lung Institute, Imperial College London, London, UK.
Platelets. 2024 Dec;35(1):2313359. doi: 10.1080/09537104.2024.2313359. Epub 2024 Feb 14.
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.
环鸟苷酸（cGMP）是一种由一氧化氮敏感的鸟苷酸环化酶（NO-GC）产生的第二信使。血小板中的 NO-GC/cGMP 通路已经得到了广泛的研究。然而，其在调节血小板生物力学特性中的作用尚未得到解决，目前仍不清楚。因此，我们使用扫描离子电导显微镜（SICM）研究了用 NO-GC 刺激剂 riociguat 或 NO-GC 激活剂 cinaciguat 处理后活血小板的刚性。用 cGMP 调节药物刺激人源和鼠源血小板可降低细胞刚性，并下调血小板活化标志物 P-选择素。我们还使用基于深度学习的血小板形态计量学来定量分析血小板形状的变化，发现用 cGMP 调节药物处理后血小板变得更圆。为了测试 NO-GC 刺激剂在增加血栓形成风险背景下的临床适用性，我们研究了 riociguat 对正在服用含有硫酸阿巴卡韦（ABC）的药物方案的 HIV 阳性患者的血小板的影响。我们的结果证实了 NO-GC/cGMP 通路在血小板生物力学中的功能作用，表明刚性或形状等生物力学特性可作为临床研究中的新型生物标志物。
