Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties.
Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties.
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DOI：
10.1523/eneuro.0378-16.2017
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发表时间：
2017-05
期刊：
影响因子：
3.4
通讯作者：
Siegenthaler JA
中科院分区：
文献类型：
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作者：
Bonney S;Siegenthaler JA
血脑屏障（BBB）是脑血管系统的多方面性质，其通过严格调节离子、分子和细胞穿过血管系统的流量来保护脑并维持体内平衡。脑中的血管由内皮细胞形成，所述内皮细胞在脑脉管系统形成后不久获得屏障性质，例如紧密连接和粘附连接。内皮WNT信号是至关重要的，以诱导这些血脑屏障的性质，通过调节其表达和稳定。最近的研究表明，维甲酸（RA）信号转导参与了BBB的发育，并表明药理学浓度的RA（≥5 µm）可诱导培养的脑内皮细胞的BBB特性。然而，最近的一项研究表明，RA在大脑发育过程中抑制内皮WNT信号传导，这表明RA不会促进BBB特性。因此，我们研究RA是否在BBB发育中起生理作用。我们发现，BBB功能和连接蛋白的表达是不受影响的小鼠突变体，具有降低的能力，合成RA（Rdh 10突变体）。此外，暴露于富含RA的饮食的胚胎没有增强BBB蛋白的表达。总之，我们的数据表明，RA是不能诱导，也不是必需的，BBB蛋白在体内的表达。与其他研究一样，我们发现药理学浓度的RA诱导培养的小鼠脑内皮细胞中的BBB基因，这可能涉及LXR/RXR信号通路的激活。我们的数据不支持RA在BBB发展中的作用，但证实了药理学RA是诱导培养中BBB特性的强大工具的报道。
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, such as 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 retinoic acid (RA) signaling in BBB development and shown that pharmacological concentrations of RA (≥5 µm) 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 whether RA plays a physiological role in BBB development. We found 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 indicate that RA is not capable of inducing, nor is it required for, BBB protein expression in vivo. Like other studies, we found that pharmacological concentrations of RA induce 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.