A first-of-its-kind study led by the University of California, Irvine has revealed a new culprit in brain hemorrhage formation that does not involve blood vessel injury, as previously believed. Researchers have discovered that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds, providing deeper insight into how they occur and identifying potential new therapeutic targets for treatment and prevention.
These results were published online recently Journal of Neuroinflammation, the team was able to see how red blood cells get stuck in brain capillaries and then observe how bleeding occurs. Cerebral microbleeds are associated with several conditions that occur at high rates in older adults, including hypertension, Alzheimer’s disease, and ischemic stroke.
We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanisms by which cerebral microbleeds develop. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhage occurring at the capillary level.”
Dr. Mark Fisher, co-corresponding author, is a professor of neurology at UCI’s School of Medicine
The team exposed red blood cells to a chemical called tert-butyl hydroperoxide, which causes oxidative stress; The cells were then labeled with a fluorescent label and injected into mice. Using two different methods, the researchers observed red blood cells getting stuck in brain capillaries and then being cleared through a process called endothelial erythrophagocytosis. As they exit the capillaries, microglia inflammatory cells engulf the red blood cells, causing brain hemorrhage.
“It has always been assumed that for cerebral hemorrhage to occur, blood vessels must be injured or disrupted. We found that the interaction of red blood cells with brain capillaries represents an alternative source of growth development,” said co-corresponding author Jiangmin. Xu, UCI professor of anatomy and neurobiology and director of the campus’s Center for Neural Circuit Mapping. “We need to examine in detail the regulation of brain capillary clearance and analyze how that process may be related to inadequate blood supply and ischemic stroke, the most common form of stroke, to help develop targeted treatments.”
Leveraging the extensive, collaborative infrastructure and robust resources of the Center for Neural Circuit Mapping, other team members were Rachita Sumbaria, co-first author/co-corresponding author and associate professor at Chapman University School of Pharmacy; Hai Zhang, co-first author and postdoctoral researcher in UCI’s Department of Anatomy and Neurobiology; Rudy Chang, co-first author and Chapman University School of Pharmacy graduate student; Jiahong Sun, postdoctoral researcher at Chapman University; David Cribbs, Professor-in-Residence at the UCI Institute for Memory Impairments and Neurological Disorders; and Todd Holmes, UCI professor of physiology and biophysics.
This work was supported by the National Institute on Aging under award numbers R01AG062840, R01AG072896, R35127102, RF1 AG065675 and R01NS121246 and the National Institute of Neurological Disorders and Stroke grant R01NS2098.