Study identifies molecular drivers of cerebral small vessel disease

A new study identifies molecular factors that promote small vessel disease - and an active drug that can restore impaired vascular functions.

Researchers at the LMU University Hospital have uncovered how diseases of the brain's small blood vessels arise. Cerebral small vessel disease can lead to widespread consequences such as impaired blood flow, hemorrhages, and often severe strokes; it is also considered one of the leading causes of dementia. The scientists' findings have now been published in the journal Nature Neuroscience.

Given the frequency of this serious and potentially life-threatening condition - strokes, for example, are the most common cause of long-term disability and the second leading cause of death - it is remarkable, says Professor Martin Dichgans, Director of the Institute for Stroke and Dementia Research (ISD) at LMU University Hospital Munich and incoming spokesperson of the SyNergy Cluster of Excellence, "that medicine has thus far known comparatively little about the cellular and molecular mechanisms underlying the development of cerebral small vessel disease." On the one hand, it is nearly impossible to directly study the tiny vessels in the human brain. On the other, there have been very few suitable experimental models that allow researchers to investigate what exactly happens at the cellular or molecular level in small vessel disease, whether in vitro or in living organisms.

In recent years, however, the Munich research team has genetically modified mice so that only their endothelial cells lack the ability to produce certain proteins. Endothelial cells form the innermost lining of blood vessels, where blood flows along - and they are the site where the disease often begins. By selectively switching off the Foxf2 gene - previously identified by the researchers as a stroke risk gene - these cells lack the corresponding protein, leading to impaired function of small cerebral vessels, especially disruption of the blood-brain barrier, which protects the brain from harmful influences.

This means, that the absence of Foxf2 is without doubt one of the fundamental causes of cerebral small vessel disease."

Professor Martin Dichgans, Director of the Institute for Stroke and Dementia Research (ISD), LMU University Hospital Munich

Foxf2 is a transcription factor that activates many other genes - including, as the Munich researchers discovered, the gene Tie2 and its downstream components in the so-called Tie signaling pathway. In endothelial cells, activation of the Tie2 gene and proper functioning of the Tie2 pathway are crucial for maintaining vascular health. Without Tie2, for example, the risk of inflammatory reactions in the endothelial cells of larger vessels increases, which in turn promotes atherosclerosis and raises the risk of stroke and dementia. "We verified our findings at multiple molecular levels," says Dichgans, "and they were confirmed in experiments with human cells as well" in collaboration with Professor Dominik Paquet another senior author of the paper.

Last but not least, the researchers tested a therapy targeting the impaired function of small cerebral vessels based on their new insights. The drug candidate AKB-9778 specifically activates Tie2. "Through treatment, we were not only able to normalize the Tie2 signaling pathway but also to restore the impaired vessel function," says the LMU neurologist. This therapy could potentially also reduce the risk of stroke and dementia.

"I would love to announce that we are already preparing a clinical study to test this compound in patients," Dichgans adds. "However, at the moment it is not easy to access the substance, as it is currently being evaluated in clinical trials for use in other conditions." The team is now searching for related compounds that could be developed for clinical testing in small vessel disease.

"I would love to announce that we are already preparing a clinical study to test this compound in patients," Dichgans adds. "However, at the moment it is not easy to access the substance, as it is currently being evaluated in clinical trials for use in other conditions." The team is now searching for related compounds that could be developed for clinical testing in small vessel disease.