Baello Stephanie, Iqbal Majid, Kearney Samantha, Kuthiala Shikah, Bloise Enrrico, Gibb William, Matthews Stephen G
a Department of Physiology , University of Toronto , Toronto , ON , Canada .
b Department of Morphology , Federal University of Minas Gerais , Belo Horizonte , Brazil .
Growth Factors. 2016 Feb;34(1-2):33-41. doi: 10.3109/08977194.2016.1162163. Epub 2016 Apr 28.
Transforming growth factor-β1 (TGF-β1) increases P-glycoprotein (P-gp; encoded by Abcb1) activity in fetal brain endothelial cells (BECs). P-gp is important for fetal brain protection against xenobiotics including synthetic glucocorticoids (sGC). We hypothesized that antenatal sGC would modify P-gp responsiveness to TGF-β1 in fetal BECs. Pregnant guinea pigs were treated with dexamethasone or vehicle (N = 5/group) on gestational day (GD) 48-49 and BECs derived on GD50. In BECs from control fetuses, TGF-β1 increased Abcb1 mRNA and P-gp function, by approximately 5-fold and 55% respectively, as well as tight junction function. In contrast, TGF-β1 had no effect on these parameters in BECs from sGC-exposed fetuses. Moreover, levels of TGF-β1 responsive gene, Smad7, were increased 3-fold in BECs from control fetuses after TGF-β1 but not in sGC-exposed fetuses. In conclusion, antenatal sGC alters responsiveness to TGF-β1 in fetal BECs. This study has identified novel mechanisms by which TGF-β1 and sGC modulate fetal brain protection against xenobiotics and other P-gp substrates.
转化生长因子-β1（TGF-β1）可增强胎脑内皮细胞（BECs）中P-糖蛋白（P-gp；由Abcb1编码）的活性。P-gp对于胎儿大脑抵御包括合成糖皮质激素（sGC）在内的外源性物质具有重要作用。我们推测产前使用sGC会改变胎BECs中P-gp对TGF-β1的反应性。妊娠豚鼠在妊娠第48 - 49天接受地塞米松或赋形剂治疗（每组N = 5），并在第50天获取BECs。在对照胎儿的BECs中，TGF-β1使Abcb1 mRNA和P-gp功能分别增加约5倍和55%，同时增强紧密连接功能。相比之下，TGF-β1对暴露于sGC的胎儿的BECs中的这些参数没有影响。此外，TGF-β1处理后，对照胎儿的BECs中TGF-β1反应性基因Smad7的水平增加了3倍，但在暴露于sGC的胎儿中未增加。总之，产前使用sGC会改变胎BECs对TGF-β1的反应性。本研究确定了TGF-β1和sGC调节胎儿大脑抵御外源性物质及其他P-gp底物的新机制。
