2. Academic Validation
  3. PI3KC2β inactivation stabilizes VE-cadherin junctions and preserves vascular integrity

PI3KC2β inactivation stabilizes VE-cadherin junctions and preserves vascular integrity

  • EMBO Rep. 2021 Jun 4;22(6):e51299. doi: 10.15252/embr.202051299.
Typhaine Anquetil 1,  Romain Solinhac 1,  Aude Jaffre 1,  Gaëtan Chicanne 1,  Julien Viaud 1,  Jean Darcourt 1,  Cyrille Orset 2,  Eva Geuss 3,  Christoph Kleinschnitz 4,  Bart Vanhaesebroeck 5,  Denis Vivien 2 6,  Karim Hnia 1,  Vincent Larrue 1 7,  Bernard Payrastre 1 8,  Marie-Pierre Gratacap 1
Affiliations

Affiliations

  • 1 INSERM, UMR-S U1297 and University of Toulouse III, Institute of Cardiovascular and Metabolic Diseases (I2MC), CHU-Rangueil, Toulouse, France.
  • 2 INSERM, UMR-S U1237 and Caen-Normandie University, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Caen, France.
  • 3 Department of Neurology, University of Würzburg, Würzburg, Germany.
  • 4 Department of Neurology, Essen University Hospital, Essen, Germany.
  • 5 Cell Signaling, UCL Cancer Institute, University College London, London, UK.
  • 6 CHU Caen, Department of Clinical Research, Caen University Hospital, Caen, France.
  • 7 Department of Neurology, University Hospital of Toulouse, Toulouse, France.
  • 8 Laboratoire d'Hématologie, CHU de Toulouse, Toulouse Cedex, France.
PMID: 33880878 DOI: 10.15252/embr.202051299
Abstract

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.

Keywords

endosomal trafficking; endothelial hyperpermeability; phosphoinositide 3-kinase C2β; vascular biology; vascular endothelial-cadherin.

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