PI3KC2β inactivation stabilizes VE‐cadherin junctions and preserves vascular integrity

Endothelium protection is critical, because of the impact of vascular leakage and edema on pathological conditions such as brain ischemia. Whereas deficiency of class II phosphoinositide 3‐kinase alpha (PI3KC2α) results in an increase in vascular permeability, we uncover a crucial role of the beta i...

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Published in:EMBO reports 2021-06, Vol.22 (6), p.e51299-n/a
Main Authors: Anquetil, Typhaine, Solinhac, Romain, Jaffre, Aude, Chicanne, Gaëtan, Viaud, Julien, Darcourt, Jean, Orset, Cyrille, Geuss, Eva, Kleinschnitz, Christoph, Vanhaesebroeck, Bart, Vivien, Denis, Hnia, Karim, Larrue, Vincent, Payrastre, Bernard, Gratacap, Marie‐Pierre
Format: Article
Language:English
Subjects:
Adherens Junctions - metabolism
Animal models
Animals
Antigens, CD - metabolism
Blood
Blood-brain barrier
Brain
Cadherins
Cadherins - genetics
Cadherins - metabolism
Capillary Permeability
Cell junctions
Cerebral infarction
Deactivation
Edema
endosomal trafficking
Endosomes
Endothelial cells
Endothelial Cells - metabolism
endothelial hyperpermeability
Endothelium
Endothelium, Vascular - metabolism
Inactivation
Infarction
Inflammation
Inflammatory response
Integrity
Ischemia
Kinases
Leakage
Lesions
Mice
Microvasculature
Permeability
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
phosphoinositide 3‐kinase C2β
Protein turnover
Reperfusion
Stroke
Therapeutic applications
Therapeutic targets
vascular biology
vascular endothelial‐cadherin
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Summary:Endothelium protection is critical, because of the impact of vascular leakage and edema on pathological conditions such as brain ischemia. Whereas deficiency of class II phosphoinositide 3‐kinase alpha (PI3KC2α) results in an increase in vascular permeability, we uncover a crucial role of the beta isoform (PI3KC2β) in the loss of endothelial barrier integrity following injury. Here, we studied the role of PI3KC2β in endothelial permeability and endosomal trafficking in vitro and in vivo in ischemic stroke. Mice with inactive PI3KC2β showed protection against vascular permeability, edema, cerebral infarction, and deleterious inflammatory response. Loss of PI3KC2β in human cerebral microvascular endothelial cells stabilized homotypic cell–cell junctions by increasing Rab11‐dependent VE‐cadherin recycling. These results identify PI3KC2β as a potential new therapeutic target to prevent aggravating lesions following ischemic stroke. SYNOPSIS This study reveals that PI3KC2β inactivation in mice confers protection against blood brain barrier leakage and inflammation in stroke models, thereby identifying PI3KC2β as a potential therapeutic target for treatment of ischemic injury. PI3KC2β inactivation preserves blood brain barrier integrity against reperfusion lesions in mice models of ischemic stroke. Mice with an inactive PI3KC2β are protected against vascular permeability, edema, cerebral infarction and inflammation in ischemia/reperfusion stroke model. PI3KC2β knockdown in endothelial cells promotes expansion of very early (APPL1+) endosomes, favor recycling endosomes (Rab11+) and enhances VE‐cadherin expression at the plasma membrane. This study reveals that PI3KC2β inactivation in mice confers protection against blood brain barrier leakage and inflammation in stroke models, thereby identifying PI3KC2β as a potential therapeutic target for treatment of ischemic injury.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.202051299