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p75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte–endothelial crosstalk in diabetes after limb ischaemia
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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 and Emanueli, Costanza (2015) p75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte–endothelial crosstalk in diabetes after limb ischaemia. Nature Communications, 6 (1). 8024 . doi:10.1038/ncomms9024
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Official URL: http://dx.doi.org/10.1038/ncomms9024
Abstract
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.
| Item Type: | Journal Article | ||||||
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| Divisions: | Faculty of Medicine > Warwick Medical School | ||||||
| Journal or Publication Title: | Nature Communications | ||||||
| Publisher: | Nature Publishing Group | ||||||
| ISSN: | 2041-1723 | ||||||
| Official Date: | 13 August 2015 | ||||||
| Dates: |
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| Volume: | 6 | ||||||
| Number: | 1 | ||||||
| Article Number: | 8024 | ||||||
| DOI: | 10.1038/ncomms9024 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Open Access |
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