Hou X, Gobeil F, Peri K, Speranza G, Marrache A M, Lachapelle P, Roberts J, Varma D R, Chemtob S, Ellis E F
Centre de Recherche de l'Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal, Montréal, Québec, Canada.
Stroke. 2000 Feb;31(2):516-24; discussion 525. doi: 10.1161/01.str.31.2.516.
Oxidant stress, especially in the premature, plays a major role in the pathogenesis of hypoxic-ischemic encephalopathies mostly manifested in the periventricular region. We studied the vasomotor mode of actions of the peroxidation product 15-F(2t)-isoprostane (15-F(2t)-IsoP) (8-iso-prostaglandin F(2alpha)) on periventricular region during development.
Effects of 15-F(2t)-IsoP on periventricular microvessels of fetal, newborn, and juvenile pigs were studied by video imaging and digital analysis techniques. Thromboxane formation and intracellular Ca(2+) were measured by radioimmunoassay and by using the fluorescent indicator fura 2-AM.
15-F(2t)-IsoP-mediated constriction of periventricular microvessels decreased as a function of age such that in the fetus it was approximately 2.5-fold greater than in juvenile pigs. 15-F(2t)-IsoP evoked more thromboxane formation in the fetus than in the newborn, which was greater than that in the juvenile periventricular region; this was associated with immunoreactive thromboxane A(2) (TXA(2)) synthase expression in the fetus that was greater than that in newborn pigs, which was greater than that in juvenile pigs. 15-F(2t)-IsoP-induced vasoconstriction was markedly inhibited by TXA(2) synthase and receptor blockers (CGS12970 and L670596). Vasoconstrictor effects of the TXA(2) mimetic U46619 on fetal, neonatal, and juvenile periventricular microvessels did not differ. 15-F(2t)-IsoP increased TXA(2) synthesis by activating Ca(2+) influx through non-voltage-gated channels in endothelial cells (SK&F96365 sensitive) and N-type voltage-gated channels (omega-conotoxin sensitive) in astrocytes; smooth muscle cells were not responsive to 15-F(2t)-IsoP but generated Ca(2+) transients to U46619 via L-type voltage-sensitive channels.
15-F(2t)-IsoP causes periventricular brain region vasoconstriction in the fetus that is greater than that in the newborn, which in turn is greater than that in the juvenile due to greater TXA(2) formation generated through distinct stimulatory pathways, including from endothelial and astroglial cells. The resulting hemodynamic compromise may contribute to the increased vulnerability of the periventricular brain areas to oxidant stress-induced injury in immature subjects.
氧化应激，尤其是在早产儿中，在缺氧缺血性脑病的发病机制中起主要作用，主要表现在脑室周围区域。我们研究了过氧化产物15-F(2t)-异前列腺素（15-F(2t)-IsoP）（8-异前列腺素F(2α)）在发育过程中对脑室周围区域的血管舒缩作用方式。
采用视频成像和数字分析技术研究15-F(2t)-IsoP对胎儿、新生和幼年猪脑室周围微血管的影响。通过放射免疫分析法和使用荧光指示剂fura 2-AM测量血栓素的形成和细胞内Ca(2+)。
15-F(2t)-IsoP介导的脑室周围微血管收缩随年龄增加而降低，在胎儿中其收缩程度比幼年猪大2.5倍左右。15-F(2t)-IsoP在胎儿中诱发的血栓素形成比新生猪更多，新生猪又比幼年脑室周围区域更多；这与胎儿中免疫反应性血栓素A(2)（TXA(2)）合酶的表达高于新生猪，新生猪又高于幼年猪有关。15-F(2t)-IsoP诱导的血管收缩被TXA(2)合酶和受体阻滞剂（CGS12970和L670596）显著抑制。TXA(2)模拟物U46619对胎儿、新生儿和幼年脑室周围微血管的血管收缩作用无差异。15-F(2t)-IsoP通过激活内皮细胞中非电压门控通道（对SK&F96365敏感）和星形胶质细胞中N型电压门控通道（对ω-芋螺毒素敏感）的Ca(2+)内流来增加TXA(2)合成；平滑肌细胞对15-F(2t)-IsoP无反应，但通过L型电压敏感通道对U46619产生Ca(2+)瞬变。
15-F(2t)-IsoP导致胎儿脑室周围脑区血管收缩程度大于新生猪，新生猪又大于幼年猪，这是由于通过不同刺激途径（包括来自内皮细胞和星形胶质细胞）产生更多的TXA(2)。由此导致的血流动力学损害可能导致未成熟个体脑室周围脑区对氧化应激诱导损伤的易感性增加。
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