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  • Shear stress control of vascular leaks and atheromas through Tie2 activation by VE-PTP sequestration.

Shear stress control of vascular leaks and atheromas through Tie2 activation by VE-PTP sequestration.

EMBO molecular medicine (2023-02-07)
Keisuke Shirakura, Peter Baluk, Astrid F Nottebaum, Ute Ipe, Kevin G Peters, Donald M McDonald, Dietmar Vestweber
ABSTRACT

Vascular endothelial protein tyrosine phosphatase (VE-PTP) influences endothelial barrier function by regulating the activation of tyrosine kinase receptor Tie2. We determined whether this action is linked to the development of atherosclerosis by examining the influence of arterial shear stress on VE-PTP, Tie2 activation, plasma leakage, and atherogenesis. We found that exposure to high average shear stress led to downstream polarization and endocytosis of VE-PTP accompanied by Tie2 activation at cell junctions. In aortic regions with disturbed flow, VE-PTP was not redistributed away from Tie2. Endothelial cells exposed to high shear stress had greater Tie2 activation and less macromolecular permeability than regions with disturbed flow. Deleting endothelial VE-PTP in VE-PTPiECKO mice increased Tie2 activation and reduced plasma leakage in atheroprone regions. ApoE-/- mice bred with VE-PTPiECKO mice had less plasma leakage and fewer atheromas on a high-fat diet. Pharmacologic inhibition of VE-PTP by AKB-9785 had similar anti-atherogenic effects. Together, the findings identify VE-PTP as a novel target for suppression of atherosclerosis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
SU1498, ≥98% (HPLC)
Sigma-Aldrich
Anti-Phosphotyrosine Antibody, clone 4G10®, clone 4G10®, Upstate®, from mouse
Sigma-Aldrich
Anti-Tie2/TEK Antibody, clone Ab33, clone Ab33, Upstate®, from mouse
Sigma-Aldrich
Tamoxifen, ≥99%
Sigma-Aldrich
Hydroxy-Dynasore, ≥98% (HPLC)
Sigma-Aldrich
Anti-VE-Cadherin Antibody, clone Vli37, culture supernatant, clone Vli37, from rabbit