Researchers here identify FOXF2 as necessary to maintain function of the vascular endothelium that lines blood vessels and the blood-brain barrier that wraps blood vessels passing through the brain to protect the distinct environment of the brain from cells and molecules that would disrupt it. They hypothesize that reduced levels of FOXF2 or related dysfunction in the expression and activity of genes it influences, such as TIE2, are an important contribution to the vascular dysfunctions that make up cerebral small vessel disease.
Researchers have 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 and they are the site where small vessel 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.
Foxf2 is a transcription factor that activates many other genes – including, as 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.
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. “I would love to announce that we are already preparing a clinical study to test this compound in patients. 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.
