Homing in on an underlying cause of stroke, scientists deliberately narrowed their focus: from the blood-brain barrier, to the blood-brain barrier’s unique capillaries, to the capillaries’ specialized cells, and—finally—to the cells’ transcriptional products. Ultimately, the scientists singled out a transcription factor that appears to coordinate biochemical events that support the development and maintenance of the blood-brain barrier. Without this transcription factor, which is called Foxf2, the blood-brain barrier is compromised, possibly to the point of failure—stroke.
This finding, which emerged from studies with mice, indicates that the variants in the Foxf2 gene could be related to stroke susceptibility in humans. That is the conclusion reached by geneticist Peter Carlsson, Ph.D., and his research team at the University of Gothenburg.
Dr. Carlsson’s team published its findings June 25 in the journal Developmental Cell, in an article entitled, “Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier.” The article noted that special cells called pericytes are well known for their role in the development of the blood-brain barrier and cerebrovascular maturation. The article added that while pericytes are also found in other organs, CNS pericytes are unique. What makes them different has been poorly understood.
The Gothenburg research team has found that the brain's pericytes contain a protein, Foxf2, which is not present in the pericytes of other organs, and which coordinates the changes that make the blood vessels compact. FoxF2 is needed in order for the blood-brain barrier to form during fetal development.
“Foxf2−/− embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky [blood-brain barrier],” the authors wrote. “Foxf2−/− brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfrβ.
The authors added that Foxf2−/− CNS vasculature has reduced Pdgfrβ and Tgfβ-Smad2/3 signaling, and that inactivation of Foxf2 in adult mice leads to breakdown of the blood-brain barrier. “Mice that have too little or too much Foxf2 develop various types of defects in the brain's blood vessels,” explained Dr. Carlsson.
One gene may play a critical role In humans, researchers have noted that major changes in a region of chromosome 6 have been associated with an increased risk of stroke, but it has not been known which of the genes in the area are responsible for this risk.
“The Foxf2 gene is an extremely interesting candidate, as it is located right in the middle of this region,” added Dr. Carlsson. “Research is under way now in collaboration with clinical geneticists to investigate the extent to which variations in the Foxf2 gene affect people's risk of suffering a stroke.”