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Platelets are best known as the cellular mediator of haemostasis and thrombosis. They also possess immune and inflammatory functions that contribute to many vascular pathologies, including atherogenesis, vascular remodelling, valvar calcification, and atherothrombosis. Platelet activation is a complex process that requires intracellular signal transduction initiated and then amplified by surface receptors for platelet agonists and involves active rearrangement of the actin cytoskeleton. Dynamic rearrangement of the actin cytoskeleton underlie the production of functional platelets by megakaryocytes as well as the secretion of platelet granules, platelet shape change, spreading, and aggregation events necessary for proper haemostasis. Among the cytoskeletal regulatory proteins, members of the Rho family of GTP binding proteins, RhoA, Rac1, and Cdc42 have emerged as critical regulators of platelet function. These small GTPases have overlapping redundancies in signalling processes, but also exhibit distinct features. Thus, RhoA governs platelet contractility and thrombus stability, Rac1 drives lamellipodia formation and Cdc42 may play predominant roles in filopodia formation and granule secretion. Megakaryocyte-specific RhoA deficiency results in thrombocytopenia and defective platelet activation. The most studied downstream effectors of RhoA are the two isoforms of Rho-associated coiled-coil containing kinase (ROCK), ROCK1, and ROCK2, members of the AGC family of serine/threonine kinases. Genetic deletion studies have shown that ROCK1 and ROCK2 mediate diverse functions in different cell types. Extending these studies, Sladojevic et al. provide evidence that ROCK2 plays a pivotal role in platelet activation and thrombosis, but does not mediate platelets’ contribution to atherosclerotic lesion and vascular remodelling. Sladojevic et al. developed mice with megakaryocyte-specific deletion of ROCK2 (ROCK2). ROCK2 deficiency leads to increased size of resting platelets and impairs cytoskeletal rearrangement that occurs during platelet activation. Loss of platelet ROCK2 leads decreased aIIbb3 integrin binding to fibrinogen and reduced expression of CD62P (P-selectin) without affecting surface expression of major glycoproteins. These findings would indicate a role for ROCK2 in the initial activation of aIIbb3 and triggering the release of CD62P from a-granules, rather than maintenance of receptor activation on activated platelets. Consequently, ROCK2-deficient platelets form considerably lesser amounts of heterotypic (platelets and leucocytes) and homotypic aggregates than wild-type ones. Using the ferric chloride-induced carotid artery injury model, the authors show that platelet-specific loss of ROCK2 decreases thrombus formation in situ. Likewise, in a model of acute thrombo-embolic stroke evoked by injection of pre-formed blood clots from wild-type or ROCK2 mice into the middle cerebral artery, ROCK2-deficient thrombotic clots are less stable and consequently, cause less cerebral injury and neurological deficits. ROCK2 mice displays slight macrothrombocytopenia, forming about 80% of the numbers of platelets relative to wild-type mice. Although the underlying mechanism is unknown, these observations would suggest a limited contribution of ROCK2 signalling to platelet generation as opposed to the dual requirement for Rac1 and Cdc42 for proper platelet production. The modest 20% reduction of platelet count in ROCK2 mice is unlikely by itself to affect primary haemostasis, indicating that the antithrombotic action of ROCK2 deficiency can be attributed to inhibition of platelet function. These findings underscore the importance of platelet ROCK2 in thrombosis and thrombo-embolic stroke and are consistent with increased ROCK activity detected in experimental models of vascular inflammation, and patients with acute ischemic strokes. An obvious limitation of the study of Sladojevic et al. is that it provides no information on how platelet ROCK2 deficiency leads to protection against thrombo-embolic stroke. Furthermore, the authors’ observations do not exclude a role for ROCK in the vessel wall, which may be activated by mediators released from platelets. Clinical studies have shown that antiplatelet therapy is associated with systemic anti-inflammatory actions in patients with atherothrombotic disease. One perspective is to investigate whether genetic deletion or pharmacological blockade of ROCK2 could also activate anti-inflammatory mechanisms. The RhoA-ROCK signalling pathway has extensively been studied. Like ROCK2, ROCK1 also triggers phosphorylation of myosin-binding subunit of myosin light chain phosphatase (MYPT1) that drives actin remodelling events. It is unclear why ROCK1 does not compensate for loss of ROCK2. Interestingly, ROCK2-deficient platelets also exhibit slightly reduced ROCK1 expression. Whether ROCK2 regulates

Context-dependent signalling in platelets in vascular diseases: ROCK2 around thrombosis