Summary: A new study reveals how blood vessels help protect the brain during inflammation. The findings could help in the development of new treatments for neurodegenerative and autoimmune diseases.
Source: University of British Columbia.
Researchers from the University of British Columbia have discovered how blood vessels protect the brain during inflammation–a finding that could lead to the development of new treatments for neurodegenerative diseases such as stroke, epilepsy and multiple sclerosis.
In a study published today in the Proceedings of the National Academy of Sciences, the researchers describe how podocalyxin, a protein in blood vessels, plays a key role in preventing harmful blood components from leaking into the brain during inflammation in response to infection or injury.
The discovery marks the first time scientists have understood the function of podocalyxin in the blood-brain barrier–a membrane that separates the brain from blood circulating in the rest of the body and that is essential for maintaining healthy brain function. Disruption of this barrier is common in neurodegenerative diseases and contributes to disease symptoms.
“These findings are incredibly exciting,” said Jessica Cait, the study’s lead author and a graduate research student at the Biomedical Research Centre at UBC. “For the first time, we have been able to show that this protein is critical to the integrity of the blood-brain barrier.”
To conduct the study, the researchers performed an analysis of the effects of podocalyxin loss in human endothelial cells, as well as in mouse models of inflammation. They were able to show that endothelial cells, which provide the inner tubing of blood vessels, require podocalyxin to strengthen blood vessels. The protein helps generate tight contacts between the cells so that potentially harmful blood components or bacterial and viral toxins can’t permeate brain tissue during times of inflammation.
“Until now, the function of this protein was a mystery,” said Dr. Michael Hughes, co-lead author and a research associate at the Biomedical Research Centre. “Nobody thought to look at this as something controlling the blood-brain barrier.”
The researchers hope their findings will lead to the development of new drugs and treatments for preventing blood-brain barrier breakdown. They have also started manipulating podocalyxin to control opening the blood-brain barrier.
“A significant hindrance to treating neurodegenerative diseases at the moment is that most drugs can’t cross the blood-brain barrier,” said Dr. Kelly McNagny, the study’s senior author and a professor in UBC’s department of medical genetics and the School of Biomedical Engineering. “But if we are able to induce transient opening of the blood-brain barrier, that could allow us to deliver treatment directly to brain tissue.”
The study was co-authored by researchers at ICORD in the Blusson Spinal Cord Centre at Vancouver General Hospital, the Centre for Heart and Lung Innovation at St Paul’s Hospital, the Djavad Mowafaghian Center for Brain Health and the Life Sciences Institute at UBC, as well as researchers at the University of Alberta.
Funding: It was supported by funding from the Canadian Institutes of Health Research.
Source: Cheryl Rossi – University of British Columbia
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Podocalyxin is required for maintaining blood–brain barrier function during acute inflammation” by Jessica Cait, Michael R. Hughes, Matthew R. Zeglinski, Allen W. Chan, Sabrina Osterhof, R. Wilder Scott, Diana Canals Hernaez, Alissa Cait, A. Wayne Vogl, Pascal Bernatchez, T. Michael Underhill, David J. Granville, Timothy H. Murphy, Calvin D. Roskelley, and Kelly M. McNagny in PNAS. Published February 20 2019.
Podocalyxin is required for maintaining blood–brain barrier function during acute inflammation
Podocalyxin (Podxl) is broadly expressed on the luminal face of most blood vessels in adult vertebrates, yet its function on these cells is poorly defined. In the present study, we identified specific functions for Podxl in maintaining endothelial barrier function. Using electrical cell substrate impedance sensing and live imaging, we found that, in the absence of Podxl, human umbilical vein endothelial cells fail to form an efficient barrier when plated on several extracellular matrix substrates. In addition, these monolayers lack adherens junctions and focal adhesions and display a disorganized cortical actin cytoskeleton. Thus, Podxl has a key role in promoting the appropriate endothelial morphogenesis required to form functional barriers. This conclusion is further supported by analyses of mutant mice in which we conditionally deleted a floxed allele of Podxl in vascular endothelial cells (vECs) using Tie2Cre mice (PodxlΔTie2Cre). Although we did not detect substantially altered permeability in naïve mice, systemic priming with lipopolysaccharide (LPS) selectively disrupted the blood–brain barrier (BBB) in PodxlΔTie2Cre mice. To study the potential consequence of this BBB breach, we used a selective agonist (TFLLR-NH2) of the protease-activated receptor-1 (PAR-1), a thrombin receptor expressed by vECs, neuronal cells, and glial cells. In response to systemic administration of TFLLR-NH2, LPS-primed PodxlΔTie2Cre mice become completely immobilized for a 5-min period, coinciding with severely dampened neuroelectric activity. We conclude that Podxl expression by CNS tissue vECs is essential for BBB maintenance under inflammatory conditions.