Summary: New research from the University of British Columbia shows how blood vessels help protect the brain during inflammation. The discovery identifies a blood-vessel protein that preserves the blood–brain barrier and may guide the development of treatments for stroke, epilepsy, multiple sclerosis and other neurodegenerative or autoimmune conditions.
Source: University of British Columbia
Blood vessels and the blood–brain barrier: how podocalyxin protects the brain during inflammation
Researchers at the University of British Columbia have identified a crucial role for the protein podocalyxin in maintaining the blood–brain barrier during acute inflammation. Published in the Proceedings of the National Academy of Sciences, the study reveals that podocalyxin, expressed on the luminal surface of blood vessel endothelial cells, helps prevent harmful blood components and microbial toxins from leaking into brain tissue when the body is fighting infection or responding to injury.
Maintaining a functional blood–brain barrier (BBB) is essential for normal brain activity. When that barrier is disrupted, blood-borne proteins, immune cells and toxins can enter the brain and contribute to neuronal dysfunction and the progression of many neurological disorders. The new findings explain how podocalyxin contributes to BBB integrity and why its presence becomes particularly important under inflammatory conditions.
Key findings
The researchers used a combination of experiments in cultured human endothelial cells and genetically modified mouse models to determine the effects of podocalyxin loss. In human endothelial cell assays, removal of podocalyxin impaired the cells’ ability to form a tight, continuous barrier. Monolayers lacking podocalyxin showed disrupted adherens junctions, reduced focal adhesions and a disorganized actin cytoskeleton—features that undermine vessel stability and barrier function.
In mice engineered to lack podocalyxin specifically in vascular endothelial cells, the BBB appeared stable under resting conditions. However, when the animals were systemically primed with an inflammatory stimulus (lipopolysaccharide, or LPS), the BBB became selectively vulnerable and breached in the absence of podocalyxin. The investigators then demonstrated functional consequences of that breach: when a thrombin receptor agonist (TFLLR-NH2) was given to LPS-primed mice lacking endothelial podocalyxin, the animals experienced a brief period of complete immobilization that coincided with reduced neuroelectric activity, indicating a transient but severe disruption of brain function.
Mechanism and implications
Podocalyxin appears to support the morphogenesis and physical contacts between endothelial cells that are necessary to form a tight vascular barrier. By promoting stable adherens junctions, focal adhesions and an ordered cortical actin network, podocalyxin strengthens the vessel wall so that blood components and pathogen-derived toxins are kept out of delicate neural tissue during inflammatory episodes.
The clinical implications are twofold. First, understanding how podocalyxin preserves BBB integrity could reveal new therapeutic targets to prevent barrier breakdown in neurodegenerative and autoimmune diseases where inflammation contributes to pathology. Second, controlled, transient manipulation of podocalyxin or related pathways might provide a strategy to temporarily open the BBB to deliver drugs directly to the brain—overcoming a major obstacle for treating central nervous system disorders.
Research team, support and publication
The study was led by Jessica Cait (graduate research student) and co-led by Michael Hughes (research associate) at UBC’s Biomedical Research Centre, with senior authorship from Dr. Kelly McNagny of UBC’s Department of Medical Genetics and the School of Biomedical Engineering. Co-authors include investigators from ICORD at the Blusson Spinal Cord Centre, the Centre for Heart and Lung Innovation at St. Paul’s Hospital, the Djavad Mowafaghian Centre for Brain Health, the Life Sciences Institute at UBC, and collaborators at the University of Alberta.
Funding: The work was supported by the Canadian Institutes of Health Research.
Abstract summary
Podocalyxin (Podxl) is broadly expressed on the luminal face of most blood vessels, but its function in endothelial cells has been unclear. The study demonstrates that Podxl is essential for endothelial morphogenesis required to form functional barriers: endothelial cells lacking Podxl fail to establish efficient barrier properties on multiple extracellular matrix substrates and show loss of junctional structures and a disordered actin cortex. In mice with conditional deletion of Podxl in vascular endothelial cells, systemic inflammatory priming selectively disrupts the blood–brain barrier, and the resulting breach produces measurable impairments in neuroelectric activity and behavior when challenged. These results indicate that Podxl expression by central nervous system endothelial cells is critical for maintaining BBB function during acute inflammation.
This improved understanding of how blood vessels defend the brain under inflammatory stress offers a promising path for therapies that either protect the BBB in disease or safely open it for targeted drug delivery.