Platelet Mechanotransduction: Regulatory Cross Talk Between Mechanosensitive Receptors and Calcium Channels

Abstract

Blood flow–induced hemodynamic changes result in mechanical stress on blood cells and vessel walls. Increased shear stress can activate platelets and other circulating cells, triggering the rapid activation of receptors, calcium channels, and related signaling mechanisms. Shear stress can also modify the folding of extracellular molecules and directly activate mechanosensitive receptors and calcium channels. The mechanical movement of the ECM (extracellular matrix) and the intracellular cortical actin cytoskeleton can change the conformation of platelet receptors and gate channel pores in the plasma membrane. Mechanosensitive platelet receptors and their downstream signaling events and metabolic products can also indirectly activate calcium channels. While the molecular composite of mechanotransduction pathways has been described in mammals, shear stress–induced platelet receptors and their cross talk with calcium channels have been incompletely characterized. In this review, we discuss current knowledge about the role of mechanosensitive platelet receptors and calcium channels in shear-dependent platelet activation and arterial thrombus formation.

Platelet Biorheology and Mechanobiology in Thrombosis and Hemostasis: Perspectives from Multiscale Computation

“…Under pathological high shear flows (i.e., severe stenosis) or elevated high shear conditions in blood-contacting devices (e.g., in left ventricular assist devices), platelet activation can also be mechanically augmented with limited GPIbα-A1 interactions seeing the presence of VWF cleavage [54,60,61]. These mechanical mechanisms of SIPAct may include additive membrane damage (or stress accumulation) [62,63], activation of shear-sensitive channels and pores such as Piezo1 and Pannexin-1 (Panx1) [64][65][66], and outside-in signaling via a range of transducers other than GPIbα and GPIIb-IIIa (integrin α I Ib β 3 ) [55,67]. Piezo1 is a mechanosensitive Ca 2+ permeable cation channel that may contribute to thrombus formation by promoting Ca 2+ influx under arterial shear [66], senses supraphysiological flow gradients that generate extensional strain leading to deformation in the platelet structure [68] (Figure 3b), and upregulates α I Ib β 3 signaling and promotes aggregation in hypertensive mice [69].…”

Harmonizing Magnetic Mitohormetic Regenerative Strategies: Developmental Implications of a Calcium–Mitochondrial Axis Invoked by Magnetic Field Exposure

“…Voltage-sensitive [5,6,45,57,73,75], receptor-mediated [16], and mechanosensitive [1] calcium entry pathways have been implicated in magnetoreceptive responses. As calcium channel crosstalk is known to occur and is mediated by changes in cellular membrane potential, energetics, redox status, or store-operated calcium release [74,76], these calcium pathways need not work in isolation of each other, but likely work in combination upon magnetic-related activation of the receptive channel class(es), particularly within the backdrop of cellular mechanosensitive calcium entry pathways [77,78]. One calciumpermeable cation channel has recently received recognition as part of the magnetoreception apparatus, TRPC1 [4,10,[15][16][17]20,23,65,71,79,80].…”

Research and Clinical Approaches to Assess Platelet Function in Flowing Blood

“…8 The function and signaling of these receptors have been comprehensively reviewed. 9,10 Engagement of platelet receptors by ligand triggers receptor clustering 11 and a series of intracellular signaling events involving activation of Src family and other kinases, as well as other intracellular redox and ubiquitinylation processes. 12–15 This signaling ultimately leads to platelet accumulation and secretion, degranulation, cytoskeletal rearrangement, thrombin generation, and ultimately formation of a stable thrombus that seals the site of vascular injury.…”