Neurotrophin production in brain pericytes during hypoxia: A role of pericytes for neuroprotection
Neurotrophin production in brain pericytes during hypoxia: A role of pericytes for neuroprotection
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DOI：
10.1016/j.mvr.2012.02.009
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发表时间：
2012-05-01
影响因子：
3.1
通讯作者：
Kitazono, Takanari
中科院分区：
文献类型：
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作者：
Ishitsuka, Koji;Ago, Tetsuro;Kitazono, Takanari
神经营养因子是神经元存活和死亡的重要调节因子。有证据表明，构成神经血管单位（NVU）的细胞协同介导神经元的发育、存活和再生。本研究的目的是测试脑血管细胞，内皮细胞和周细胞，是否产生神经营养素，并在缺氧损伤时发挥神经保护作用。我们研究了神经营养素及其受体在培养的人脑微血管内皮细胞和周细胞，星形胶质细胞和大鼠神经元细胞系PC 12中的表达。分化的PC 12细胞表达TrkA，神经生长因子受体，这是显着上调缺氧在1%O-2和调节神经元的存活。周细胞和星形胶质细胞都表达三种神经营养蛋白，即NGF、BDNF和NT-3，而TrkB和TrkC（BDNF和NT-3的特异性受体）在星形胶质细胞中表达，但周细胞中不表达。为了响应缺氧，在周细胞和星形胶质细胞中表达的神经营养蛋白中，只有周细胞中NT-3的表达显着上调。用NT-3处理星形胶质细胞显著激活Erk 1/2，并在mRNA和蛋白水平上增加NGF的表达。MEK 1抑制剂U 0126或siRNA介导的TrkC敲低消除了NT-3诱导的星形胶质细胞中NGF的上调。总之，脑微血管周细胞和星形胶质细胞是NVU中神经营养因子的有效生产者。作为对缺氧的反应，周细胞增加NT-3的产生，其诱导星形胶质细胞通过TrkC-Erk 1/2途径增加NGF的产生。周细胞和星形胶质细胞之间的相互作用，通过神经营养因子在NVU可能发挥重要作用，在缺氧条件下的神经元存活。(C)2012 Elsevier Inc. All rights reserved.
Neurotrophins are crucial regulators of neuronal survival and death. Evidence suggests that cells comprising the neurovascular unit (NVU) cooperatively mediate neuronal development, survival and regeneration. The aim of this study was to test whether cerebrovascular cells, endothelial cells and pericytes, produce neurotrophins and play neuroprotective roles during hypoxic insults. We examined the expression of neurotrophins and their receptors in cultured human cerebral microvascular endothelial cells and pericytes, astrocytes and the rat neuronal cell line PC12. Differentiated PC12 cells expressed TrkA, the NGF receptor, which was significantly upregulated by hypoxia at 1% O-2 and regulated neuronal survival. Both pericytes and astrocytes expressed three neurotrophins, i.e. NGF, BDNF and NT-3, while TrkB and TrkC, specific receptors for BDNF and NT-3, were expressed in astrocytes, but not pericytes. In response to hypoxia, among the neurotrophins expressed in pericytes and astrocytes only NT-3 expression was significantly upregulated in pericytes. Treatment of astrocytes with NT-3 significantly activated Erk1/2 and increased the expression of NGF both at mRNA and protein levels. The MEK1 inhibitor U0126 or siRNA-mediated knockdown of TrkC abolished the NT-3-induced upregulation of NGF in astrocytes. Taken together, cerebral microvascular pericytes and astrocytes are potent producers of neurotrophins in the NVU. In response to hypoxia, pericytes increase NT-3 production, which induces astrocytes to increase NGF production through the TrkC-Erk1/2 pathway. The interplay between pericytes and astrocytes through neurotrophins in the NVU may play an important role in neuronal survival under hypoxic conditions. (C) 2012 Elsevier Inc. All rights reserved.