Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells
Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells
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DOI：
10.1074/jbc.m404115200
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发表时间：
2004-08-06
影响因子：
4.8
通讯作者：
Madri, JA
中科院分区：
文献类型：
--
作者：
Kim, H;Li, Q;Madri, JA
脑源性神经营养因子（BDNF）由内皮细胞表达。我们研究了脑源性内皮细胞表达BDNF的特征，并验证了BDNF具有影响中枢神经系统脉管系统的旁分泌和自分泌功能的假设。除了在常氧条件下表达TrkB、p75（NTR）和BDNF外，这些细胞在缺氧条件下也增加了BDNF的表达。虽然TrkB的表达不受缺氧影响，但TrkB在常氧条件下表现出基线磷酸化，当添加BDNF时磷酸化增加。当内源性BDNF被可溶性TrkB隔离时，TrkB磷酸化降低。外源性BDNF在这些内皮细胞的三维培养中诱导了强大的血管生成和存活，而内源性BDNF的隔离导致了显著的细胞凋亡。BDNF参与TrkB的作用似乎是通过磷脂酰肌醇（PI） 3-激酶- akt途径介导的。BDNF水平的调节与Akt磷酸化直接相关，而PI 3-激酶抑制剂可消除BDNF反应。bdnf对内皮细胞存活/凋亡的影响与caspase 3的激活直接相关。这些内皮细胞也表达p75(NTR)，并通过凋亡对其首选配体，前神经生长因子（pro-NGF）作出反应。这些数据支持神经营养因子信号在中枢神经系统内皮的动态维持/分化中的作用。
Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells. We investigated the characteristics of BDNF expression by brain-derived endothelial cells and tested the hypothesis that BDNF serves paracrine and autocrine functions affecting the vasculature of the central nervous system. In addition to expressing TrkB and p75(NTR) and BDNF under normoxic conditions, these cells increased their expression of BDNF under hypoxia. While the expression of TrkB is unaffected by hypoxia, TrkB exhibits a base-line phosphorylation under normoxic conditions and an increased phosphorylation when BDNF is added. TrkB phosphorylation is decreased when endogenous BDNF is sequestered by soluble TrkB. Exogenous BDNF elicits robust angiogenesis and survival in three-dimensional cultures of these endothelial cells, while sequestration of endogenous BDNF caused significant apoptosis. The effects of BDNF engagement of TrkB appears to be mediated via the phosphatidylinositol ( PI) 3-kinase-Akt pathway. Modulation of BDNF levels directly correlate with Akt phosphorylation and inhibitors of PI 3-kinase abrogate the BDNF responses. BDNF-mediated effects on endothelial cell survival/apoptosis correlated directly with activation of caspase 3. These endothelial cells also express p75(NTR) and respond to its preferred ligand, pro-nerve growth factor (pro-NGF), by undergoing apoptosis. These data support a role for neurotrophins signaling in the dynamic maintenance/differentiation of central nervous system endothelia.