p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.
p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.
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DOI：
10.1038/ncomms9024
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发表时间：
2015-08-13
影响因子：
16.6
通讯作者：
Emanueli C
中科院分区：
文献类型：
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作者：
Caporali A;Meloni M;Nailor A;Mitić T;Shantikumar S;Riu F;Sala-Newby GB;Rose L;Besnier M;Katare R;Voellenkle C;Verkade P;Martelli F;Madeddu P;Emanueli C
微血管系统中血管内皮细胞（EC）和周细胞之间的通讯是血管生长和体内平衡的基础;然而，这些过程被糖尿病破坏。在这里，我们表明，在暴露于高葡萄糖的EC中p75 NTR表达的调节激活了miR-503的转录，这对周细胞功能产生了负面影响。p75 NTR激活NF-κB结合miR-503启动子，上调miR-503在EC中的表达。NF-κB进一步诱导Rho激酶的活化和携带miR-503的内皮微粒的脱落，其将miR-503从EC转移到血管周细胞。受体周细胞中整合素介导的miR-503摄取降低了EFNB 2和VEGFA的表达，导致迁移和增殖受损。我们证实了上述机制在糖尿病小鼠模型中的作用，其中EC衍生的miR-503减少了毛细血管的周细胞覆盖，增加了通透性，并削弱了肢体肌肉中缺血后的血管生成。总的来说，我们的数据表明，miR-503调节微血管糖尿病并发症中的周细胞-内皮串扰。 糖尿病患者的血管功能和修复受损。在此，Caporali等人报道了血管内皮细胞中神经营养因子受体的激活诱导抗血管生成miR-503，其在微粒介导的转移后损害邻近周细胞的功能。
The communication between vascular endothelial cells (ECs) and pericytes in the microvasculature is fundamental for vascular growth and homeostasis; however, these processes are disrupted by diabetes. Here we show that modulation of p75NTR expression in ECs exposed to high glucose activates transcription of miR-503, which negatively affects pericyte function. p75NTR activates NF-κB to bind the miR-503 promoter and upregulate miR-503 expression in ECs. NF-κB further induces activation of Rho kinase and shedding of endothelial microparticles carrying miR-503, which transfer miR-503 from ECs to vascular pericytes. The integrin-mediated uptake of miR-503 in the recipient pericytes reduces expression of EFNB2 and VEGFA, resulting in impaired migration and proliferation. We confirm operation of the above mechanisms in mouse models of diabetes, in which EC-derived miR-503 reduces pericyte coverage of capillaries, increased permeability and impaired post-ischaemic angiogenesis in limb muscles. Collectively, our data demonstrate that miR-503 regulates pericyte–endothelial crosstalk in microvascular diabetic complications. Vascular function and repair is impaired in patients with diabetes. Here, Caporali et al. report that activation of the neurotrophin receptor in vascular endothelial cells induces the antiangiogenic miR-503, which impairs the function of neighbouring pericytes upon microparticle-mediated transfer.