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  • The vessel wall protein collagen which becomes

    2021-10-13

    The vessel wall protein collagen, which becomes exposed to circulating platelets after vascular injuries, is a very strong platelet agonist. It stimulates all relevant platelet activation steps predominantly via the GPVI/FcRγ-chain receptor complex through an immunoreceptor tyrosine-based activation motif (ITAM)-regulated phospholipase Cγ2-dependent signaling pathway. Similarly, von Willebrand factor (vWF) and podoplanin bind to and stimulate specific platelet membrane adhesion receptors (GPIb/V/IX complex and the C-type lectin receptor CLEC-2, respectively), whereas other endogenous agonists including thrombin, ADP and TXA2 bind to and activate G-protein coupled receptors (GPCRs), see also Fig. 1 [[11], [12], [13]]. The resulting platelet activation is a multistep process, characterized by cytoskeletal rearrangements, integrin activation, granule secretion, TXA2 synthesis/release, and exposure of anionic phospholipids, leading to shape change, adhesion, aggregation and coagulation. These responses are mediated by an extensive membrane receptor-activated intracellular signaling network including many intracellular serine/threonine and tyrosine protein kinases and elevation of cytosolic Ca2+ concentration [12,14,15]. Endothelial cell-derived prostacyclin and nitric oxide (NO), by increasing the level of platelet cyclic nucleotides cAMP and cGMP, respectively, represent the two major endogenous platelet inhibitors [[16], [17], [18], [19], [20], [21], [22]]. Elevated cAMP and cGMP levels regulate specific Cetrorelix systems such as certain phosphodiesterases (PDEs; see below) and cAMP- and cGMP-dependent protein kinases A (PKA) and G (PKG) which phosphorylate multiple substrates involved in platelet inhibition (discussed below, section 5–9). In addition to vascular/endothelial-derived platelet inhibitors such as PGI2 and NO, there is increasing appreciation that there are platelet-derived inhibitory mechanisms upon platelet activation [23]. These include immunoreceptor tyrosine-based inhibitory motif containing receptors (ITIMs) such as PECAM-1, CEACAM1/2, G6b-B, intracellular receptors (PPARs, LXR, RXR, GR), negative regulators of small GTPases and integrins, protein phosphatases, and mechanisms for receptor desensitization [23].
    Functional effects of platelet cGMP elevation It was a major pharmacological discovery that nitrates, NO-releasing drugs and NO itself are potent vasodilators, platelet inhibitors and elevators of cellular cGMP levels [17,18,24,25]. Further, PDE5 inhibitors such as sildenafil potentiated the in vitro cGMP-elevating and antiaggregatory effect of NO releasing drugs such as sodium nitroprusside on platelets, but alone had no direct effect on platelet functions [26] as extended by other studies [[27], [28], [29]]. Functionally, cGMP-elevating agents, similar to cAMP-elevating agents, inhibit agonist-induced integrin activation, granule secretion, TXA2 synthesis/release and cytoskeleton rearrangement in platelets (reviewed in Refs. [19,[30], [31], [32], [33]], Fig. 1). All these steps are crucially involved in mediating platelet shape change, adhesion and aggregation, relevant for intact primary hemostasis, but also for coagulation. Coagulation is characterized by cell-based, regulated cleavage of fibrinogen to fibrin via the serine protease thrombin. Strongly activated platelets exhibit anionic phospholipids such as phosphatidylserines (PS) on their surface which enable the coordinated binding of coagulation factors to the platelet surface, leading to a burst of thrombin generation and the formation of a stable fibrin thrombus [34]. cAMP-elevating agents, such as iloprost and prostaglandin E1 (PGE1), have been shown to inhibit platelet exposure of PS and tissue factor-triggered thrombin generation [35]. NO donors and the PDE5 inhibitor sildenafil inhibit thrombin-/convulxin-induced annexin-V binding to mouse platelets of wildtype, but not sGC-deficient platelets, indicating that NO inhibits the exposure of anionic phospholipids in a cGMP-dependent manner [36]. However, the role of the sGC/cGMP/PKG system in the regulation of platelet-dependent thrombin generation needs further investigation.