Growth Differentiation Factor 11 Promotes Neurovascular Recovery After Stroke in Mice.
Growth Differentiation Factor 11 Promotes Neurovascular Recovery After Stroke in Mice.
复制标题
生长分化因子 11 促进中风后小鼠神经血管恢复
DOI：
10.3389/fncel.2018.00205
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发表时间：
2018
影响因子：
5.3
通讯作者：
Zhao BQ
中科院分区：
文献类型：
--
作者：
Lu L;Bai X;Cao Y;Luo H;Yang X;Kang L;Shi MJ;Fan W;Zhao BQ
背景：生长分化因子11(GDF11)是转化生长因子-β(TGFR-β)超家族成员之一，具有恢复心肌和骨骼肌功能，改善脑血管和神经发生的作用。然而，最近的实验数据表明，升高GDF11水平会抑制骨骼肌再生，对心肌肥大没有影响。我们的目的是研究GDF11在卒中后恢复期对脑修复的影响。方法：采用小鼠大脑中动脉远端闭塞模型，于卒中后7~13d给予重组GDF11(RGDF11)1次/d。第14天检测神经前体细胞的增殖和血管生成情况。42天后检测神经元再生情况。采用横梁行走试验和T台步走试验进行行为功能评定。对GDF11的下游途径也进行了研究。结果：卒中后14天，GDF11在同侧梗死区周围皮质和室下区表达上调。RGDF11治疗可增加新生NPC和内皮细胞的数量、微血管长度和面积以及脑毛细血管灌注量。Western blotts结果显示，rGDF11上调脑源性神经营养因子(BDNF)的表达，增加血管生成因子血管生成素-2(Ang-2)和血管内皮生长因子受体-2(VEGFR-2)的磷酸化水平。我们还发现，rGDF11上调转录因子Smad2和Smad3的磷酸化，但这些激活被转化生长因子-β受体抑制剂SB431542阻断。此外，注射SB431542可逆转rGDF11诱导的血管新生重塑和NPC增殖，提示GDF11可能通过转化生长因子-β/Smad2/3信号通路发挥作用。最后，用rGDF11治疗的小鼠在神经元再生和功能恢复方面有显著的增加。结论：GDF11可促进小鼠卒中后神经再生和血管生成，促进功能恢复。
Background: Growth differentiation factor 11 (GDF11), a member of transforming growth factor-β (TGF-β) superfamily, was shown to rejuvenate cardiac and skeletal muscle function and to improve cerebral vasculature and neurogenesis in old mice. However, recent experimental data reported that raising GDF11 levels inhibited skeletal muscle regeneration and had no effect on cardiac hypertrophy. Our aim was to investigate the effects of GDF11 on brain repair during the recovery phase after stroke. Methods: Mice were subjected to distal middle cerebral artery occlusion, and recombinant GDF11 (rGDF11) was injected intraperitoneally once a day during days 7–13 after stroke. Neuronal precursor cells (NPCs) proliferation and angiogenesis were assayed at 14 days. Neuronal regeneration was assayed at 42 days. The beam-walking test and CatWalk were used to evaluate behavioral functions. Downstream pathways of GDF11 were also investigated. Results: GDF11 was upregulated in the ipsilateral peri-infarct cortex and subventricular zone (SVZ) at 14 days after stroke. Treatment with rGDF11 enhanced the number of newborn NPCs and endothelial cells, microvascular length and area, and brain capillary perfusion. Western blots showed that rGDF11 upregulated brain-derived neurotrophic factor (BDNF) and increased the levels of proangiogenic factor angiopoietin-2 (Ang-2) and phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2). We also found that rGDF11 upregulated the transcription factors Smad2 and Smad3 phosphorylation, but these activations were blocked by a TGF-β receptor inhibitor SB431542. Moreover, rGDF11-induced angiogenic remodeling and NPCs proliferation were reversed by injection of SB431542, suggesting that GDF11 may exert its effect via the TGF-β/Smad2/3 signaling pathway. Finally, treating mice with rGDF11 resulted in a significant increase in neuronal regeneration and functional recovery. Conclusion: GDF11 promoted neurogenesis and angiogenesis and contributed to functional recovery after stroke in mice.
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影响因子：
20.1
作者：
Smith SC;Zhang X;Zhang X;Gross P;Starosta T;Mohsin S;Franti M;Gupta P;Hayes D;Myzithras M;Kahn J;Tanner J;Weldon SM;Khalil A;Guo X;Sabri A;Chen X;MacDonnell S;Houser SR
通讯作者：
Houser SR
衰老对血管生成的影响。
影响因子：
20.1
作者：
Lähteenvuo J;Rosenzweig A
通讯作者：
Rosenzweig A
影响因子：
29
作者：
Egerman MA;Cadena SM;Gilbert JA;Meyer A;Nelson HN;Swalley SE;Mallozzi C;Jacobi C;Jennings LL;Clay I;Laurent G;Ma S;Brachat S;Lach-Trifilieff E;Shavlakadze T;Trendelenburg AU;Brack AS;Glass DJ
通讯作者：
Glass DJ
影响因子：
8.3
作者：
KRUPINSKI, J;KALUZA, J;WANG, JM
通讯作者：
WANG, JM
影响因子：
6.9
作者：
Koh, Seong-Ho;Park, Hyun-Hee
通讯作者：
Park, Hyun-Hee