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New research from the University of Virginia School of Medicine has identified a function for brain immune cells that may inform efforts to support blood flow in neurodegenerative conditions.
The study, led by researchers from the Department of Neuroscience, focused on the role of microglia – immune cells known for their involvement in brain maintenance and inflammatory responses.
Findings suggest that microglia can regulate capillary “tone”, which affects how effectively blood reaches brain tissue. Impaired microglial activity could reduce nutrient and oxygen delivery to the brain, with possible implications for conditions such as Alzheimer’s disease, vascular dementia and Parkinson’s disease.
Linking immune cells to vascular function
Although previous studies have linked myeloid cells to blood vessel health, the specific mechanisms by which microglia contribute to capillary regulation remained unclear. The UVA team identified that microglia influence the diameter of capillaries, thereby affecting their capacity to deliver blood.
“For some time now, microglia have been suggested to play important roles in regulating vessel function. With this study, we have provided the most definitive evidence that they do regulate blood flow to the brain, specified the location of this function to the brain’s small vessels or capillaries and identified an enzyme that they use to do this,” said study author Ukpong B. Eyo, PhD, of UVA’s Center for Brain Immunology and Glia (BIG Center) and the UVA Brain Institute. “Although microglia are dysfunctional in neurodegenerative diseases, our work now raises the possibility of improving blood flow deficits by targeting microglia.”
In experimental models, the researchers found that removing microglia led to narrower capillaries and decreased blood flow. Reintroducing microglia restored vessel tone and improved blood delivery. The team also identified a microglial enzyme involved in this regulatory process. While this enzyme has previously been targeted in Alzheimer’s therapeutics, its role in vascular regulation presents new avenues for time-sensitive interventions.
Broader implications for neurodegeneration
Proper vascular function is crucial in the brain, which, despite comprising only 2% of body weight, consumes approximately 20% of total energy. The brain’s vascular system includes an extensive network of small vessels that must function efficiently to meet these metabolic demands.
The researchers propose that disruptions in microglial regulation of capillary tone may contribute to blood flow deficiencies commonly seen in neurodegenerative diseases. Ongoing studies are examining whether this mechanism could be leveraged to slow or reverse disease-related cognitive decline.
Future directions
The study highlights the need for further investigation into how microglia interact with other cell types to control vascular structure and function. Researchers are also exploring whether this microglial role is established early in development and how it may relate to vascular abnormalities in neurodevelopmental conditions.
“The microglial enzyme identified in this study has been targeted heretofore in patients with Alzheimer’s disease, albeit with mixed results. Our study suggests that these therapeutics would have maximal benefit if prescribed according to the therapeutic window of microglia in Alzheimer’s – a focus in our ongoing research,” said UVA researcher William A. Mills III, PhD, the study’s first author. “We have determined that all microglia are capable of regulating basal capillary tone as opposed to a subset of them, thus revealing their importance to meeting energy demands in the brain.”
The work forms part of a broader effort by UVA’s recently launched Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases. The center aims to identify disease mechanisms and develop new therapeutic strategies.
“Now that we have identified a novel role for microglia in blood vessel structure and function as well as a specific enzyme involved, we are poised to examine how this enzyme and microglial functions change, and to subsequently develop therapies to reduce these changes during neurodegenerative diseases broadly and in Alzheimer’s disease especially,” Eyo said. “However, questions abound that our group will pursue – e.g., do the microglia regulate the small capillaries independently or in concert with other brain cells? When during development do microglia begin to play this role, and is this role also important in neurodevelopmental disorders where vascular function is also compromised? Can microglial replacement facilitate blood flow rejuvenation in neurodegenerative diseases? These are exciting questions we hope to answer in the near future.”
Reference: Mills WA, Savory NA, Lopez-Ortiz AO, et al. Microglial cyclooxygenase-1 modulates cerebral capillary basal tone in vivo in mice. Nat Commun. 2025;16(1):5704. doi: 10.1038/s41467-025-60753-x
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