PI3KC2β inactivation stabilizes VE-cadherin junctions and preserves vascular integrity

Area of Science:

• Neuroscience
• Cell Biology
• Vascular Biology

Background:

• Endothelial barrier integrity is crucial for preventing vascular leakage and edema in conditions like brain ischemia.
• While PI3KC2α deficiency increases permeability, the role of PI3KC2β in endothelial barrier function was previously unclear.

Purpose of the Study:

• To investigate the role of phosphoinositide 3-kinase beta (PI3KC2β) in endothelial permeability and endosomal trafficking.
• To evaluate PI3KC2β's impact on ischemic stroke pathology in vitro and in vivo.

Main Methods:

• Utilized in vitro human cerebral microvascular endothelial cells and in vivo mouse models of ischemic stroke.
• Assessed vascular permeability, edema, cerebral infarction, and inflammatory responses.
• Investigated endosomal trafficking pathways, specifically Rab11-dependent VE-cadherin recycling.

Main Results:

• Mice lacking functional PI3KC2β were protected against stroke-induced vascular permeability, edema, and infarction.
• Loss of PI3KC2β stabilized endothelial cell-cell junctions.
• PI3KC2β inhibition enhanced Rab11-dependent VE-cadherin recycling in human cerebral microvascular endothelial cells.

Conclusions:

• PI3KC2β plays a critical role in the loss of endothelial barrier integrity following ischemic injury.
• Targeting PI3KC2β represents a promising therapeutic strategy to mitigate brain damage after ischemic stroke.