P75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia

Andrea Caporali, Marco Meloni, Audrey Nailor, Tijana Mitić, Saran Shantikumar, Federica Riu, Graciela B. Sala-Newby, Lorraine Rose, Marie Besnier, Rajesh Katare, Christine Voellenkle, Paul Verkade, Fabio Martelli, Paolo Madeddu, Costanza Emanueli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number8024
JournalNature Communications
Volume6
DOIs
Publication statusPublished - Aug 13 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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