TY - JOUR T1 - Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0378-16.2017 SP - ENEURO.0378-16.2017 AU - Stephanie Bonney AU - Julie A. Siegenthaler Y1 - 2017/05/16 UR - http://www.eneuro.org/content/early/2017/05/16/ENEURO.0378-16.2017.abstract N2 - The blood-brain barrier (BBB) is a multifaceted property of the brain vasculature that protects the brain and maintains homeostasis by tightly regulating the flux of ions, molecules and cells across the vasculature. Blood vessels in the brain are formed by endothelial cells that acquire barrier properties, like tight and adherens junctions, soon after the brain vasculature is formed. Endothelial WNT signaling is crucial to induce these BBB properties by regulating their expression and stabilization. Recent studies have implicated RA signaling in BBB development and shown that pharmacological concentrations of retinoic acid (RA) (≥5µm) can induce BBB properties in cultured brain endothelial cells. However, a recent study demonstrated that RA inhibits endothelial WNT signaling during brain development suggesting that RA does not promote BBB properties. We therefore investigated if RA plays a physiological role in BBB development. We find that BBB function and junctional protein expression was unaffected in mouse mutants that have a reduced capacity to synthesize RA (Rdh10 mutants). Furthermore, embryos exposed to a RA-enriched diet did not enhance BBB protein expression. Together, our data indicates that RA is not capable of inducing or is required for BBB protein expression in vivo. Like other studies, we find that pharmacological concentrations of RA induces BBB genes in cultured murine brain endothelial cells and this may involve activation of the LXR/RXR signaling pathway. Our data do not support a role for RA in BBB development, but confirm reports that pharmacological RA is a robust tool to induce BBB properties in culture.Significance Statement Uncovering signals that promote BBB properties in CNS blood vessels is crucial to understand how the brain vascular network supports brain function. In contrast to previous studies, we provide substantial evidence that RA signaling is not required for prenatal BBB development. However we show that pharmacological concentrations of RA (≥5μM) is a useful tool to promote BBB properties in brain ECs and that this effect may be due to LXR/RXR signaling. We have also revealed a potential independent function of LXRs in regulating the expression of BBB genes. These studies could provide insight into mechanisms that underlie the BBB breakdown that occurs in many CNS diseases and improve in vitro BBB models to study drug delivery and BBB biology. ER -