TY - JOUR
T1 - P75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia
AU - Caporali, Andrea
AU - Meloni, Marco
AU - Nailor, Audrey
AU - Mitić, Tijana
AU - Shantikumar, Saran
AU - Riu, Federica
AU - Sala-Newby, Graciela B.
AU - Rose, Lorraine
AU - Besnier, Marie
AU - Katare, Rajesh
AU - Voellenkle, Christine
AU - Verkade, Paul
AU - Martelli, Fabio
AU - Madeddu, Paolo
AU - Emanueli, Costanza
PY - 2015/8/13
Y1 - 2015/8/13
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms9024
DO - 10.1038/ncomms9024
M3 - Article
AN - SCOPUS:84939130561
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 8024
ER -