Decreased thromboembolic stroke but not atherosclerosis or vascular remodelling in mice with ROCK2-deficient platelets
| Autor: | James K. Liao, Nikola Sladojevic, Goo Taeg Oh, Karol Kamiński, Hervé Falet, Jane E. Freedman, Hyung-Hwan Kim, Lea M. Beaulieu |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Blood Platelets medicine.medical_specialty Platelet Aggregation Physiology Mice Transgenic 030204 cardiovascular system & hematology Vascular Remodeling Vascular occlusion Vascular remodelling in the embryo 03 medical and health sciences Mice 0302 clinical medicine Thrombin Physiology (medical) Internal medicine medicine.artery Invited Editorials medicine Animals Platelet Stroke rho-Associated Kinases business.industry Thrombosis Original Articles Actin cytoskeleton medicine.disease Atherosclerosis Platelet Activation Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology Middle cerebral artery Cardiology medicine.symptom Cardiology and Cardiovascular Medicine business medicine.drug |
| Zdroj: | Cardiovascular research. 113(11) |
| ISSN: | 1755-3245 |
| Popis: | Aims Rho-associated coiled-coil containing kinase (ROCK)-2 is an important mediator of the actin cytoskeleton. Because changes in the actin cytoskeleton are critical for platelet function, we hypothesized that ROCK2 in platelets will play important role in thrombosis and can be potentially a target for therapeutic intervention in thromboembolic stroke. Methods and results We generated platelet-specific ROCK2-deficient mice (ROCK2Plt-/-) from conditional ROCK2fl°x/fl°x and platelet factor (PF)-4-Cre transgenic mice. Platelets from ROCK2Plt-/- mice were less responsive to thrombin stimulation in terms of pseudopodia formation, collagen adhesion, and in the formation of homotypic and heterotypic aggregates. This corresponded to prolonged bleeding time and delayed vascular occlusion following vessel injury. To determine whether these changes in platelet function could affect thrombotic disease, we utilized a clot-embolic model of ischaemic stroke. When pre-formed clots from ROCK2Plt-/- mice were injected into the middle cerebral artery of control mice, cerebral blood flow recovery occurred more rapidly, leading to decreased cerebral injury and neurological deficits, compared to pre-formed clots from control mice. Interestingly, pre-formed clots from control mice produced similar degree of cerebral injury when injected into control or ROCK2Plt-/- mice, suggesting that platelet ROCK2 deficiency affects clot formation but not propagation. Indeed, in a non-thrombotic intra-filament MCA occlusion model of stroke, platelet ROCK2 deletion was not protective. Furthermore, ROCK2Plt-/- mice exhibit similar atherosclerosis severity and vascular remodeling as control mice. Conclusion These findings indicate that platelet ROCK2 plays important role in platelet function and thrombosis, but does not contribute to the pathogenesis of atherosclerosis and vascular remodeling. |
| Databáze: | OpenAIRE |
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