Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier

•The transcription factor Foxf2 is expressed specifically in CNS pericytes•Foxf2−/− mice have cerebrovascular defects and fail to develop a blood-brain barrier•Foxf2−/− CNS vasculature has reduced Pdgfrβ and Tgfβ-Smad2/3 signaling•Inactivation of Foxf2 in adult mice leads to breakdown of the blood-brain barrier

SummaryPericytes are critical for cerebrovascular maturation and development of the blood-brain barrier (BBB), but their role in maintenance of the adult BBB, and how CNS pericytes differ from those of other tissues, is less well understood. We show that the forkhead transcription factor Foxf2 is specifically expressed in pericytes of the brain and that Foxf2−/− embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky BBB. Foxf2−/− brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfrβ. Tgfβ-Smad2/3 signaling was attenuated, whereas phosphorylation of Smad1/5 and p38 were enhanced. Tgfβ pathway components, including Tgfβ2, Tgfβr2, Alk5, and integrins αVβ8, were reduced. Foxf2 inactivation in adults resulted in BBB breakdown, endothelial thickening, and increased trans-endothelial vesicular transport. On the basis of these results, FOXF2 emerges as an interesting candidate locus for stroke susceptibility in humans.