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| Professor Martin Dichgans Photo Credit: © LMU / Stephan Höck |
Researchers at LMU University Hospital have elucidated how diseases of small blood vessels in the brain develop. So-called cerebral small vessel disease (CSVD) can lead to widespread consequences such as circulatory disorders, hemorrhages, and often severe strokes, and is considered one of the main causes of dementia. The scientists' results have now been published in the journal Nature Neuroscience.
In view of the prevalence of this serious and life-threatening condition—strokes, for example, are the leading cause of long-term disability and the second leading cause of death—it is astonishing "that medicine has so far known comparatively little about the cellular and molecular mechanisms underlying the development of cerebral small vessel disease," says LMU Professor Martin Dichgans, Chair of Translational Stroke and Dementia Research, Director of the Institute for Stroke and Dementia Research (ISD) at LMU University Hospital Munich, and future spokesperson for the SyNergy Cluster of Excellence.
For one thing, it is hardly possible to examine the tiny vessels in the human brain directly. On the other hand, "hardly any suitable experimental models have been available until now that allow us to investigate—in the test tube or within the organism—exactly what happens at the cellular or molecular level in small vessel diseases," says Dominik Paquet, Professor of Neurobiology at the ISD.
Genetic Modification of Endothelial Cells
However, in recent years, the Munich scientists have genetically modified endothelial cells—both in mice and in a human model developed from induced pluripotent stem cells (iPS)—so that they can no longer produce certain proteins. Endothelial cells form the innermost layer of the vessel walls, along which blood flows; they are the site where the disease frequently begins.
Through the targeted silencing of the Foxf2 gene—a risk gene for stroke previously identified by the researchers—the cells lack the corresponding protein. This leads to a deterioration in the function of small brain vessels, specifically a disruption of the blood-brain barrier, which protects the brain from harmful influences. "Thus," explains Martin Dichgans, "the absence of Foxf2 is undoubtedly one of the fundamental causes of cerebral small vessel disease."
Therapeutic Options for Disrupted Signaling Pathways
Foxf2 is a transcription factor that activates many other genes—including, as the Munich researchers discovered, the Tie2 gene and its downstream genes in the so-called Tie signaling pathway. A normally activated Tie2 gene, or a normally functioning Tie2 signaling pathway in endothelial cells, is crucial for keeping vessels healthy.
Without Tie2, for example, the risk of inflammatory reactions in the endothelial cells of larger vessels increases, which in turn promotes arteriosclerosis ("hardening of the arteries") and the risk of stroke and dementia. "We have verified our results on various molecular levels," says Dichgans. "And we were also able to confirm their relevance for humans in experiments with our newly developed human blood vessel model," says Paquet.
The researchers also tested a therapy against the impaired function of small brain vessels based on their new findings. The drug compound AKB-9778 specifically activates Tie2. "Through this treatment, we were not only able to normalize the Tie2 signaling pathway but also restore impaired vascular function," says neurologist Dichgans. This therapy could potentially also reduce the risk of stroke and dementia.
"I would describe strictly speaking that we are already preparing a study with patients in which this active substance will be tested," says Dichgans, "but it is currently not quite easy to obtain the substance because it is currently being tested in clinical trials for use in eye diseases." The researchers are now looking for related active substances that might be suitable for clinical testing in small vessel diseases.
Published in journal: Nature Neuroscience
Title: The stroke risk gene Foxf2 maintains brain endothelial cell function via Tie2 signaling
Authors: Katalin Todorov-Völgyi, Judit González-Gallego, Stephan A. Müller, Mihail Ivilinov Todorov, Fatma Burcu Seker, Simon Frerich, Filippo M. Cernilogar, Luise Schröger, Rainer Malik, Jiayu Cao, Gemma Llovera, Stefan Roth, Ulrike Schillinger, Martina Schifferer, Azadeh Reyahi, Dennis Crusius, Liliana D. Pedro, Mikael Simons, Peter Carlsson, Ali Ertürk, Arthur Liesz, Gunnar Schotta, Nikolaus Plesnila, Stefan F. Lichtenthaler, Dominik Paquet, and Martin Dichgans
Source/Credit: Ludwig-Maximilians-Universität München | Translation Scientific Frontline
Reference Number: ns121525_01
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