TGF-β1 Regulation of Multidrug Resistance P-glycoprotein in the Developing Male Blood-Brain Barrier
TGF-β1 Regulation of Multidrug Resistance P-glycoprotein in the Developing Male Blood-Brain Barrier
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DOI：
10.1210/en.2013-1472
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发表时间：
2014-02-01
期刊：
影响因子：
4.8
通讯作者：
Matthews, Stephen G.
中科院分区：
文献类型：
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作者：
Baello, Stephanie;Iqbal, Majid;Matthews, Stephen G.
P-糖蛋白（P-gp）是由abcb1基因编码的外排转运蛋白，保护发育中的胎儿脑。血脑屏障（BBB）内皮细胞中的P-gp水平在脑生长高峰期显著增加。这与星形胶质细胞和神经元增加TGF-β 1的释放相一致。虽然TGF-β 1已被证明可以调节许多细胞类型中的P-gp活性，但对TGF-β 1如何调节脑保护知之甚少。在本研究中，我们假设TGF-β 1以年龄依赖性方式增加胎儿和出生后血脑屏障中abcb1的表达和P-gp活性。我们发现TGF-β 1可有效调节abcb1 mRNA和P-gp功能。TGF-β 1增加了胎鼠和出生后雄性豚鼠脑内皮细胞（BECs）中P-gp的功能。与出生后获得的BEC相比，这些影响在妊娠早期更为明显。为了研究所涉及的信号通路，将妊娠第50天和出生后第14天的BEC暴露于ALK 1和ALK 5抑制剂和激动剂。通过抑制ALK 5，我们证明了ALK 5是TGF-β 1对P-gp功能的影响所必需的。通过激动剂BMP-9激活ALK 1，产生与TGF-β 1对P-gp功能相似的结果。然而，通过ALK 1途径的TGF-β 1信号传导是年龄依赖性的，因为dorsomorphin，一种ALK 1抑制剂，在出生后第14天的BEC中减弱了TGF-β 1介导的作用，但在妊娠第50天的BEC中则没有。总之，TGF-β 1调节胎儿和新生儿BBB的P-gp，ALK 5和ALK 1通路均参与P-gp功能的调节。在发育中的血脑屏障中TGF-β 1水平的异常可能导致胎儿脑暴露于P-gp底物的实质性变化，从而引发脑发育的后果。
P-glycoprotein (P-gp), an efflux transporter encoded by the abcb1 gene, protects the developing fetal brain. Levels of P-gp in endothelial cells of the blood-brain barrier (BBB) increase dramatically during the period of peak brain growth. This is coincident with increased release of TGF-beta 1 by astrocytes and neurons. Although TGF-beta 1 has been shown to modulate P-gp activity in a number of cell types, little is known about how TGF-beta 1 regulates brain protection. In the present study, we hypothesized that TGF-beta 1 increases abcb1 expression and P-gp activity in fetal and postnatal BBB in an age-dependent manner. We found TGF-beta 1 to potently regulate abcb1 mRNA and P-gp function. TGF-beta 1 increased P-gp function in brain endothelial cells (BECs) derived from fetal and postnatal male guinea pigs. These effects were more pronounced earlier in gestation when compared with BECs derived postnatally. To investigate the signaling pathways involved, BECs derived at gestational day 50 and postnatal day 14 were exposed to ALK1 and ALK5 inhibitors and agonists. Through inhibition of ALK5, we demonstrated that ALK5 is required for the TGF-beta 1 effects on P-gp function. Activation of ALK1, by the agonist BMP-9, produced similar results to TGF-beta 1 on P-gp function. However, TGF-beta 1 signaling through the ALK1 pathway is age-dependent as dorsomorphin, an ALK1 inhibitor, attenuated TGF-beta 1-mediated effects in BECs derived at postnatal day 14 but not in those derived at gestational day 50. In conclusion, TGF-beta 1 regulates P-gp at the fetal and neonatal BBB and both ALK5 and ALK1 pathways are implicated in the regulation of P-gp function. Aberrations in TGF-beta 1 levels at the developing BBB may lead to substantial changes in fetal brain exposure to P-gp substrates, triggering consequences for brain development.