PI3KC2β inactivation stabilizes VE‐cadherin junctions and preserves vascular integrity.

Autor: 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
Zdroj: EMBO Reports; 6/4/2021, Vol. 22 Issue 6, p1-18, 18p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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