Leaky blood vessels in the brain linked to Rett syndrome: Study
Leakage driven by elevated levels of microRNA molecule tied to gene activity
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MIT researchers have discovered that tiny blood vessels in the brains of people with Rett syndrome may be more permeable, or “leaky,” according to a new study.
Using miniature models of blood vessel systems built with cells derived from Rett patients, the team found that this leakage was driven by elevated levels of microRNA-126-3p, a small microRNA molecule that regulates gene activity in endothelial cells lining blood vessels. When researchers lowered microRNA-126-3p levels, the leakage slowed.
Researchers noted that a potential therapy that suppresses microRNA-126 is currently under development for leukemia, a type of blood cancer. Thus, expanding this therapy into Rett syndrome may be a promising therapeutic approach to vascular impairment.
“A role for microRNAs in Rett syndrome has been shown, but now demonstrating that [microRNA-126-3p] is … directly implicated in the endothelial cell dysfunction is an important piece of the Rett syndrome puzzle,” Mriganka Sur, PhD, a professor of neuroscience in the Picower Institute and MIT’s department of brain and cognitive sciences, and a senior author of the study, said in a university news story.
The study, “miR126-mediated alteration of vascular integrity in Rett syndrome,” was published in Molecular Psychiatry.
Researchers engineered a microvascular network in the lab
Rett syndrome is a rare neurodevelopmental disorder primarily affecting girls. It’s characterized by normal early development followed by a loss of purposeful hand skills, speech, and motor coordination, usually between 6 and 18 months of age. Most cases are caused by mutations in the MECP2 gene, which disrupts normal brain development.
Beyond the brain, reduced MeCP2 protein activity can affect other cell types, including endothelial cells that line blood vessels. Research shows that children with Rett often have poor circulation and reduced blood flow in certain parts of the brain. The period when Rett children begin to lose previously learned skills, usually between ages 1 and 4, coincides with a critical stage of brain blood vessel growth.
To learn more about vascular changes in Rett, he researchers engineered a microvascular network in the lab using stem cells from Rett patients carrying common MECP2 mutations. These cells were programmed to become endothelial cells and then grown in 3D microfluidic devices to form vessel-like networks.
Compared with networks built from genetically corrected control cells, Rett‑derived networks showed significantly higher permeability — meaning molecules moved more freely across the vessel wall, a sign of a weakened barrier.
This permeability defect was further supported by differences in the production of tight junction proteins such as ZO-1, which help hold endothelial cells together. The Rett networks had lower ZO-1 levels, consistent with a compromised barrier.
“That’s why we hypothesized that we should have some mediator between the MeCP2 mutation and ZO-1 downregulation and the [blood vessel] permeability increase,” said Tatsuya Osaki, PhD, the study’s lead author. “We focused on the microRNAs.”
Potential therapy for leukemia may also show promise for Rett
Similar problems were seen in a more advanced lab model that included astrocytes, support cells that help form the blood-brain barrier, which tightly controls what substances enter and leave the brain.
To explore how these vascular changes might affect brain function, the researchers exposed nerve cells to fluid from the Rett blood vessel cultures. The neurons showed reduced electrical activity, suggesting that factors released by Rett endothelial cells may interfere with normal nerve signaling.
Using gene expression (activity) profiling and RNA sequencing, the team found that endothelial cells derived from Rett patients had significantly higher levels of microRNA-126-3p (miR-126-3p) than controls. MicroRNAs are short RNA molecules that regulate gene expression, often lowering the activity of target genes.
And, elevated miR-126-3p, expressed exclusively in endothelial cells, appeared to lower the activity of several genes involved in maintaining vascular integrity and stabilizing the blood vessel wall.
Further tests confirmed that higher miR-126-3p directly drove blood vessel permeability. The team used a molecule to selectively reduce miR-126-3p levels in Rett endothelial cells. This approach partially restored the barrier and increased the expression of markers showing tight junctions between cells.
The researchers noted that the miR-126 inhibitor, miRisten, is currently in clinical trials for leukemia, thus “expanding its application from leukemia to Rett syndrome may be a promising therapeutic approach to treat Rett syndrome associated with vascular impairment.”
“Overall, our findings point to miR126-3p-mediated vascular impairment in [Rett] patients and suggest potential therapeutic approaches for restoring function,” the team added.
