Abstract 51: A Critical Role for Outside-In Signaling of Integrin AlphalIIIb/Beta3 in Shear-Dependent Platelet Microvesicle Formation and Phosphatidylerine Exposure
| Autor: | Aleksandra Stojanovic-Terpo, Aiming Pang, Xiaoping Du, Michael K Delaney, Yujie Cui |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 37 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.37.suppl_1.51 |
| Popis: | Platelets promote coagulation mainly by exposing membrane phosphatidylserine (PS) and releasing PS-expressing microvesicles (MV). We have recently shown that PS exposure and MV release induced by platelet agonists requires shear stress. To identify the receptor responsible for the shear-dependent signaling leading to PS exposure and MV release, we compared platelets from β 3 -/- mice and wild-type mice in MV release and PS exposure under defined shear stress introduced using a cone-plate rheometer. MV release and PS exposure were determined using flow cytometry. Shear-dependent PS exposure and MV release were significantly suppressed in β 3 -/- platelets. Similarly, Wild type platelets treated with integrin antagonists also showed defective PS exposure and MV release. These data indicate an important role for the ligand binding function of integrin αιιb/β3 in shear-dependent MV release and PS exposure. To determine whether the role of integrin αιιb/β3 is due to its outside-in signaling, β 3 -/- platelets were transplanted with wild type β 3 or a mutant β 3 with the critical Gα13 binding site of the β 3 cytoplasmic domain (EEE) changed to alanines (AAA), which was previously shown to selectively abolish outside-in signaling of αIIb/β 3 . Transplantation of wild type β 3 rescued the defective MVs release and PS exposure of β 3 -/- platelets. In contrast, AAA mutant failed to rescue these defects. Consistently, wild type platelets treated with the selective inhibitor of Gα13-integrin interaction, inhibited integrin outside-in signaling and also PS exposure and MV release under shear stress. Furthermore, we also showed that the inhibition of Src, which is important in outside-in signaling downtream of Gα13, also abolished shear-dependent MV release and PS exposure. These data suggest that integrin outside-in signaling mediated by the Gα13-β 3 interaction and Src-dependent signaling pathway plays an important role in transmitting shear-induced mechanical signals leading to MV release and PS exposure in activated platelets. |
| Databáze: | OpenAIRE |
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