Role of Sox17 transcription factor In blood brain barrier integrity

Abstract

Blood-brain barrier (BBB) featuring mature brain vessels maintains neural homeostasis by limiting the influx of toxins and pathogens into brain tissues. While the formation and maturation of BBB have been elucidated fairly well, how BBB is maintained during adulthood, especially in hypertensive stress remains elusive. Transcription factor Sox17, which is important for vascular development, shows robust expression in endothelial cells in adult brain capillaries. To know the role of Sox17 in the maintenance of brain capillaries under hypertensive condition, we excised Sox17 from endothelial cells in adult mice infused with angiotensin II (AT II). We found that endothelial Sox17 deficiency resulted in AT II-induced leakage from brain vessels. The leakage was the mostly abundant in thalamus, which is the most frequent area for hypertension related intracranial hemorrhage. Under AT II infusion, Sox17-deficient thalamic vessels showed destabilized tight junction and enhanced transcytosis. Sox17-deficient thalamic endothelial cells had increased senescent-associated $\beta$-galactosidase activity and p16ink4a expression under AT II, suggesting endothelial senescence as one of mechanisms for BBB disruption. Importantly, co-deletion of p16 rescued the integrity of brain vessels. These results suggest that endothelial Sox17 protect BBB integrity from hypertensive stress by suppressing stress-induced premature senescence.