p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.,Nature Communications

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p75(NTR)-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia.
Nature Communications ( IF 14.7 ) Pub Date : 2015-Aug-13 , DOI: 10.1038/ncomms9024
Andrea Caporali _{1,

2} , Marco Meloni ₁ , Audrey Nailor ₁ , Tijana Mitić ₁ , Saran Shantikumar ₁ , Federica Riu ₁ , Graciela B Sala-Newby ₁ , Lorraine Rose ₂ , Marie Besnier ₁ , Rajesh Katare ₁ , Christine Voellenkle ₃ , Paul Verkade ₄ , Fabio Martelli ₃ , Paolo Madeddu ₁ , Costanza Emanueli _{1,

5}

Affiliation

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 p75(NTR) expression in ECs exposed to high glucose activates transcription of miR-503, which negatively affects pericyte function. p75(NTR) 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.

中文翻译：

p75(NTR) 依赖性 NF-κB 激活可调节糖尿病肢体缺血后的 microRNA-503 转录和周细胞内皮串扰。

微血管系统中血管内皮细胞 (EC) 和周细胞之间的通讯对于血管生长和稳态至关重要。然而，这些过程会被糖尿病破坏。在这里，我们表明，在暴露于高葡萄糖的 EC 中调节 p75（NTR）表达会激活 miR-503 的转录，从而对周细胞功能产生负面影响。 p75(NTR) 激活 NF-κB 结合 miR-503 启动子并上调 EC 中 miR-503 的表达。 NF-κB 进一步诱导 Rho 激酶激活和携带 miR-503 的内皮微粒脱落，从而将 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 EFNB2 和 VEGFA 的表达，导致迁移和增殖受损。我们在糖尿病小鼠模型中证实了上述机制的运作，其中 EC 衍生的 miR-503 减少了毛细血管的周细胞覆盖，增加了渗透性并损害了肢体肌肉的缺血后血管生成。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。

更新日期：2015-08-17

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