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

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 transc...

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Bibliographic Details
Published in:Nature communications 2015-08, Vol.6, p.8024-8024
Main Authors: Caporali, Andrea, Meloni, Marco, Nailor, Audrey, Mitić, Tijana, Shantikumar, Saran, Riu, Federica, Sala-Newby, Graciela B, Rose, Lorraine, Besnier, Marie, Katare, Rajesh, Voellenkle, Christine, Verkade, Paul, Martelli, Fabio, Madeddu, Paolo, Emanueli, Costanza
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - metabolism
Endothelial Cells - metabolism
Gene Expression Regulation - physiology
Hindlimb - blood supply
Humans
Ischemia
Male
Mice
Mice, Knockout
MicroRNAs - genetics
MicroRNAs - metabolism
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
NF-kappa B - genetics
NF-kappa B - metabolism
Oligonucleotide Array Sequence Analysis
Pericytes - physiology
Receptors, Nerve Growth Factor - genetics
Receptors, Nerve Growth Factor - metabolism
Transcription, Genetic - physiology
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Summary: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.
ISSN:2041-1723
DOI:10.1038/ncomms9024