Brain-derived neurotrophic factor stimulates production of prostacyclin in cerebral arteries.
Brain-derived neurotrophic factor stimulates production of prostacyclin in cerebral arteries.
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DOI：
10.1161/strokeaha.109.564492
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发表时间：
2010-02
期刊：
影响因子：
8.3
通讯作者：
Katusic ZS
中科院分区：
文献类型：
--
作者：
Santhanam AV;Smith LA;Katusic ZS
脑源性神经营养因子（BDNF）及其受体原肌球蛋白受体激酶B（Trk B）在脑循环控制中的作用知之甚少。本研究旨在探讨BDNF在体内的脑血管效应。将编码大鼠脑源性神经营养因子（BDNF）或绿色荧光蛋白（GFP）的复制缺陷型腺病毒（AdBDNF）注入家兔脑池内。48小时后，对动物实施安乐死。采用ELISA法检测血浆和脑脊液中BDNF的含量，采用器官腔法检测离体基底动脉的血管功能，采用Western blotting法检测基底动脉中蛋白表达，采用ELISA法检测前列腺素的含量，采用放射免疫法检测环磷酸腺苷（cAMP）的含量。AdBDNF治疗组兔脑脊液中BDNF含量显著高于AdGFP治疗组（37 ± 5 ng/ml vs.0.006 ± 0.003ng/ml，P<0.05，n=14）。Western blotting研究显示，在基底动脉中，AdBDNF增加前列环素（PGI 2）合酶的蛋白表达，而内皮型一氧化氮合酶（eNOS）和磷酸化（Ser 1177）eNOS的表达保持不变。在花生四烯酸（1 μmol/L）孵育期间，仅AdBNP处理的兔基底动脉中PGI 2产生和环磷酸腺苷水平显着升高（P<0.05，n=6）。注射AdBDNF的家兔基底动脉对乙酰胆碱（10−9 ~ 10−5 mol/L）和花生四烯酸（10−9 ~ 10−5 mol/L）的舒张作用显著增强。非选择性环氧合酶抑制剂吲哚美辛（10−5 mol/L，P<0.05，n=6）和组成型磷脂酶A2抑制剂AACOCF 3（2 × 10−5 mol/L，P <0.05，n=5）可抑制AdBDNF处理的基底动脉对乙酰胆碱的舒张作用。我们的研究结果表明，在脑动脉中，BDNF诱导的TrkB受体信号的激活在体内促进PGI 2的生物合成。这些发现为BDNF在脑循环中的血管保护作用提供了新的机制。
The role of Brain Derived Neurotrophic Factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), in control of cerebral circulation is poorly understood. The present study was designed to investigate the cerebral vascular effects of BDNF in vivo. Replication incompetent adenovirus encoding either rat BDNF (AdBDNF) or green fluorescent protein (AdGFP) was injected intracisternally into rabbits. Forty eight hours later, animals were euthanized. Plasma and cerebrospinal fluid (CSF) levels of BDNF were measured by ELISA, vasomotor function of isolated basilar arteries was studied in organ chambers, protein expression in the basilar arteries was studied by Western blotting, prostanoid levels measured by ELISA and cyclic adenosine 3′,5′-monophosphate (cyclic AMP) levels were measured by radioimmunoassay. The levels of BDNF in the CSF were significantly elevated in AdBDNF-treated rabbits as compared to AdGFP-treated rabbits (37 ± 5 ng/ml vs. 0.006 ± 0.003 ng/ml, respectively, P<0.05, n=14). Western blotting studies revealed that in basilar arteries AdBDNF increased protein expression of prostacyclin (PGI2) synthase, while expression of endothelial nitric oxide synthase (eNOS) and phosphorylated (Ser 1177) eNOS remained unchanged. During incubation with arachidonic acid (1 μmol/L), PGI2 production and levels of cyclic AMP were significantly elevated only in AdBDNF-treated rabbit basilar arteries (P<0.05, n=6). Relaxations to acetylcholine (10−9 to 10−5 mol/L) and arachidonic acid (10−9 to 10−5 mol/L) were significantly potentiated in basilar arteries from rabbits injected with AdBDNF. Potentiation of relaxations to acetylcholine in AdBDNF-treated basilar arteries was inhibited by the non-selective cyclooxygenase inhibitor, indomethacin (10−5 mol/l, P<0.05, n=6) and constitutive phospholipase A2 inhibitor, AACOCF3 (2 × 10−5 mol/L, P<0.05, n=5). Our results demonstrate that in cerebral arteries, BDNF-induced activation of TrkB receptor signaling in vivo promotes PGI2 biosynthesis. These findings provide novel mechanistic insight into vascular protective effect of BDNF in cerebral circulation.