July 23, 2024

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Molecular causes of common cerebrovascular diseases

Molecular causes of common cerebrovascular diseases


Molecular causes of common cerebrovascular diseases.  Cerebral cavernous malformations (CCM) are dilated clusters of thin-walled blood vessels in the brain that can cause strokes and seizures, but how they form is still a mystery.

Molecular causes of common cerebrovascular diseases

A research team at the Perelman School of Medicine at the University of Pennsylvania has discovered the molecular mechanism of this common cerebrovascular disease. They published the results of the study in Nature magazine online this week.


CCM disease occurs in about 100 to 200 people, and it can appear in two forms. One is sporadic, accounting for 80% of cases, and is most common in the elderly. The remaining 20% ​​are family genetic cases.

These patients exhibit a large number of lesions, and more severe symptoms appear in much younger individuals. CCM disease is a progressive disease, and its standard of care is still surgical resection of the most dangerous lesions and symptom management.

When CCM was initially identified as a genetic disease, a mutation in one of the two copies of the three genes was identified in human patients.

It has been found that the proteins encoded by these genes bind to each other in a single complex, but this complex lacks intrinsic enzyme activity. How does its loss lead to vascular disease-and why this vascular disease occurs so specifically in the brain-still Not sure.

“Although we don’t know much about CCM, how the loss of the CCM complex causes disease is still controversial, and many downstream signaling pathways and processes have been proposed to play a role,” senior author Mark Kahn, MD, Edward S. Cooper, MD / Norman Roosevelt Elizabeth Meriwether McLure is a professor of medicine.

When studying the development of the vertebrate heart, an important clue to the pathogenesis of the disease was discovered. At that time, Kahn’s laboratory found that the CCM protein in endothelial cells controls the activity of the enzyme MEKK3 and the downstream gene expression program, which is essential for the normal development of the embryonic heart. Important.


For nature research, Kahn’s laboratory investigated whether conservative mechanisms may also be the basis for the formation of CCM damage in the postpartum brain.

They used a neonatal mouse CCM disease model and found that the expression of MEKK3 target genes KLF2 and KLF4 increased in the newly formed CCM diseased cells. “From there, we were able to prove that the specific loss of the endothelium of MEKK3, KLF2 or KLF4 genes can completely rescue the formation of lesions and prevent mice from dying due to CCM disease,” Kahn said.


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