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 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.
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.|University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Andrea
A
Caporali
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Marco
M
Meloni
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Audrey
A
Nailor
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Tijana
T
Mitić
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Saran
S
Shantikumar
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Federica
F
Riu
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Graciela B
GB
Sala-Newby
University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Lorraine
L
Rose
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Marie
M
Besnier
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Rajesh
http://orcid.org/0000-0001-5419-7935
R
Katare
Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan 20097, Italy.
Christine
C
Voellenkle
Wolfson Bioimaging Facility, University of Bristol, Bristol BS2 8HW, UK.
Paul
P
Verkade
Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan 20097, Italy.
Fabio
F
Martelli
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.
Paolo
P
Madeddu
School of Clinical Sciences, Bristol Heart Institute, Bristol BS2 8HW, UK.|National Institute of Heart and Lung, Imperial College of London, London SW7 2AZ, UK.
Costanza
C
Emanueli
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020286:Pericytes / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
C545473:MIRN503 microRNA, human; D035683:MicroRNAs; C556275:Mirn503 microRNA, mouse; D016328:NF-kappa B; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse