In mice, cMAF, a protein that regulates gene activity, helps immune cells surrounding cerebral arteries maintain vascular responses to CO2 and cerebrospinal fluid flow
In mice, cMAF, a protein that regulates gene activity, helps immune cells surrounding cerebral arteries maintain vascular responses to CO2 and cerebrospinal fluid flow
On August 14, the authors of an article described this mechanism. Perivascular macrophages, immune cells located around cerebral arteries, depend on cMAF. When the researchers disabled this protein in mice, they disrupted both the movement of cerebrospinal fluid, which surrounds the brain, and the vascular response to excess carbon dioxide.
Cerebrospinal fluid moves partly through spaces along large arteries. In 2022, researchers showed that perivascular macrophages contribute to this movement. The new study examined which genetic program maintains the state of these cells and allows them to influence blood vessels.
The authors compared gene activity across different brain macrophage populations and identified cMAF. They then disabled Maf, the gene that encodes this protein, in mice. The macrophages surrounding the arteries lost their characteristic pattern of active genes, and the influx of a fluorescent tracer along the middle cerebral artery decreased during the first 28 minutes after its injection into the cerebrospinal fluid.
The authors examined how this change affected vascular function by giving the mice a mixture containing 10% CO2. In control animals, the arteries dilated and cerebral blood flow increased. After cMAF was disabled, both responses disappeared. In the first genetic model, the intervention also affected microglia, another type of immune cell in the brain. A separate experiment targeting perivascular macrophages also found an impaired cerebral blood flow response.
IGF1 provided the link between the macrophages and the blood vessels. This signaling protein acts on cells in the inner lining of arteries through the IGF1R receptor. Macrophages with active cMAF produced IGF1. Selective deletion of Igf1 in brain macrophages reproduced the impaired arterial dilation and cerebral blood flow response to CO2. In this mouse model, cMAF maintains the macrophage state, IGF1 carries the macrophage signal to the inner lining of the vessel, and the artery responds to excess CO2.
In single-nucleus gene activity data from the human brain, MAF was the most active regulator in the corresponding population of perivascular macrophages. In carriers of the APOE3 gene variant, MAF and IGF1 activity in these cells increased together with amyloid deposition. A genetic variant near MAF was associated with both higher activity of this gene and a lower risk of Alzheimer's disease.