Podocalyxin is required for maintaining blood-brain barrier function during acute inflammation

Area of Science:

• Vascular Biology
• Cellular Biology
• Neuroscience

Background:

• Podocalyxin (Podxl) is expressed on blood vessel endothelial cells, but its specific function is not well understood.
• Endothelial barrier integrity is vital for organ function, particularly the blood-brain barrier (BBB).

Purpose of the Study:

• To investigate the role of Podxl in maintaining endothelial barrier function.
• To determine the impact of Podxl deficiency on the blood-brain barrier under inflammatory conditions.

Main Methods:

• Utilized electrical cell-substrate impedance sensing and live imaging to assess endothelial barrier function in vitro.
• Generated and analyzed conditional knockout mice (PodxlΔTie2Cre) lacking Podxl in vascular endothelial cells (vECs).
• Administered lipopolysaccharide (LPS) and a protease-activated receptor-1 (PAR-1) agonist to assess BBB integrity and neurological function in vivo.

Main Results:

• Podxl-deficient endothelial cells failed to form efficient barriers, exhibiting disorganized actin cytoskeleton, and lacking adherens and focal adhesions.
• Conditional deletion of Podxl in vECs led to selective disruption of the BBB in LPS-primed mice.
• Systemic administration of a PAR-1 agonist in LPS-primed PodxlΔTie2Cre mice caused immobilization and dampened neuroelectric activity, indicating severe BBB breach.

Conclusions:

• Podxl is essential for endothelial cell morphogenesis and the formation of functional endothelial barriers.
• Podxl expression in CNS vascular endothelial cells is critical for maintaining BBB integrity during inflammation.
• Podxl deficiency compromises the BBB, leading to neurological deficits under inflammatory stress.