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• W3029799735 abstract "Background Alteration in hemodynamic shear stress at atheroprone sites promotes endothelial paracellular pore formation and permeability. The molecular mechanism remains unknown. Methods and Results We show that Nck (noncatalytic region of tyrosine kinase) deletion significantly ameliorates disturbed flow‐induced permeability, and selective isoform depletion suggests distinct signaling mechanisms. Only Nck1 deletion significantly reduces disturbed flow‐induced paracellular pore formation and permeability, whereas Nck2 depletion has no significant effects. Additionally, Nck1 re‐expression, but not Nck2, restores disturbed flow‐induced permeability in Nck1/2 knockout cells, confirming the noncompensating roles. In vivo, using the partial carotid ligation model of disturbed flow, Nck1 knockout prevented the increase in vascular permeability, as assessed by Evans blue and fluorescein isothiocyanate dextran extravasations and leakage of plasma fibrinogen into the vessel wall. Domain swap experiments mixing SH 2 (phosphotyrosine binding) and SH 3 (proline‐rich binding) domains between Nck1 and Nck2 showed a dispensable role for SH 2 domains but a critical role for the Nck1 SH 3 domains in rescuing disturbed flow‐induced endothelial permeability. Consistent with this, both Nck1 and Nck2 bind to platelet endothelial adhesion molecule‐1 ( SH 2 dependent) in response to shear stress, but only Nck1 ablation interferes with shear stress–induced PAK 2 (p21‐activated kinase) membrane translocation and activation. A single point mutation into individual Nck1 SH 3 domains suggests a role for the first domain of Nck1 in PAK recruitment to platelet endothelial cell adhesion molecule‐1 and activation in response to shear stress. Conclusions This work provides the first evidence that Nck1 but not the highly similar Nck2 plays a distinct role in disturbed flow‐induced vascular permeability by selective p21‐activated kinase activation." @default.
• W3029799735 created "2020-06-05" @default.
• W3029799735 creator A5001589730 @default.
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• W3029799735 date "2020-06-02" @default.
• W3029799735 modified "2023-10-14" @default.
• W3029799735 title "Nck1, But Not Nck2, Mediates Disturbed Flow‐Induced p21‐Activated Kinase Activation and Endothelial Permeability" @default.
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• W3029799735 doi "https://doi.org/10.1161/jaha.120.016099" @default.
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