When someone has an ischemic stroke, doctors work swiftly to remove the arterial blockage and restore blood flow to the brain. But sometimes even once the blockage is removed, there's lasting - sometimes fatal - damage.
Every minute when someone's brain is not getting enough blood flow carrying oxygen and glucose, they're losing neurons. But how much? How many? And can you get them back?"
John Chappell, assistant professor, Fralin Biomedical Research Institute, VTC's Center for Heart and Reparative Medicine Research
These are just some of the questions motivating one of Chappell's research projects, which was recently awarded a three-year $300,000 American Heart Association Transformational Project Award.
"When blood flow stops abruptly during an ischemic stroke, the microvasculature within the affected regions becomes dangerously fragile," said Chappell, who is also an assistant professor in Virginia Tech's Department of Biomedical Engineering and Mechanics.
Clots can form either in the brain, or in vessels located elsewhere in the body before traveling to the brain. If doctors try to restore blood flow to injured brain tissue by removing the blockage and increasing blood pressure, the capillaries are likely to rupture and hemorrhage - causing even more damage to the patient.
"What makes these vessels become so fragile?" asked Chappell.
That's where a cell type known as a pericyte comes into play.
Pericytes span along multiple endothelial cells, the innermost lining of blood vessels. They provide stability, keep blood vessels sealed tight, help regulate blood flow, and play a key role in upholding the blood-brain barrier.
In healthy, perfused blood vessels, the endothelium receives information from molecules in the blood and then sends signals to neighboring pericytes through specifically arranged "peg and socket" gap junctions.
"What we want to know is how this interaction changes when blood flow stops. Our hypothesis is that when blood flow stops, these gap junctions are dissolved as the cells prepare to remodel," said Chappell. "But if there is a way to keep those gap junctions intact, maintain pericyte stability, and strengthen the vessel, then that could potentially guide the development of next-generation stroke therapies."
Over the next three years, Chappell's team will look for molecular targets - such as connexin proteins that make up the gaps junctions or chemicals transferred through blood - that might play a role in preserving gap junctions and reinforcing vascular stability.
Chappell is collaborating on this project with Michelle Theus, an associate professor at the Virginia-Maryland College of Veterinary Medicine, and Biraj Patel, a neurointerventional radiologist at Carilion Clinic.