Abstract 51: A Critical Role for Outside-In Signaling of Integrin AlphalIIIb/Beta3 in Shear-Dependent Platelet Microvesicle Formation and Phosphatidylerine Exposure
Abstract only 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 shea...
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Published in | Arteriosclerosis, thrombosis, and vascular biology Vol. 37; no. suppl_1 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
01.05.2017
|
Online Access | Get full text |
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Abstract | Abstract only
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. |
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AbstractList | Abstract only
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. |
Author | Pang, Aiming Delaney, Michael K Stojanovic-Terpo, Aleksandra Du, Xiaoping Cui, Yujie |
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Snippet | Abstract only
Platelets promote coagulation mainly by exposing membrane phosphatidylserine (PS) and releasing PS-expressing microvesicles (MV). We have... |
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Title | Abstract 51: A Critical Role for Outside-In Signaling of Integrin AlphalIIIb/Beta3 in Shear-Dependent Platelet Microvesicle Formation and Phosphatidylerine Exposure |
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