Molecular mechanisms of extracellular vesicle-induced vessel destabilization in diabetic retinopathy.
OBJECTIVE
Diabetic retinopathy (DR) is characterized by early dropout of capillary pericytes, leading to loss of control on endothelial proliferation and, subsequently, angiogenesis. We have demonstrated that extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) maintained in diabetic-like conditions may play a role in vessel destabilization, thus contributing to angiogenesis through paracrine signalling. In particular, a role for MMP-2 was described. This study was aimed at further investigating the molecular mechanisms of EV-induced vessel destabilization.


METHODS
We evaluated miR-126 expression, the subsequent HIF-1α and VEGF modulation, Ang-2 and PDGF signalling pathways in human retinal pericytes (HRP) after exposure to MSC-derived EV obtained in diabetic-like conditions (high glucose and/or hypoxia).


RESULTS
HRP express miR-126, and this expression is down-regulated in intermittent high glucose. MSC-derived EV obtained in hyperglycaemic/hypoxic conditions down-regulate miR-126 expression in pericytes, leading to increased expression of angiogenic molecules, such as VEGF and HIF-1α. No modulation of Ang-2 and PDGF signalling pathways in pericytes was observed following EV exposure.


CONCLUSIONS
HRP express miR-126, and this expression is down-regulated in diabetic-like conditions. Exposure of HRP to EV obtained in diabetic-like conditions is able to decrease miR-126 expression, consistently with previous observations of its involvement in DR and providing further insights into the role of EV in vessel destabilization. In contrast, PDGF and Ang-2 signalling pathways do not seem to be involved in these mechanisms.
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
Aurora
A
Mazzeo
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy. elena.beltramo@unito.it.
Elena
E
Beltramo
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
Alessandra
A
Iavello
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
Andrea
A
Carpanetto
Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy.
Massimo
M
Porta
D000804:Angiotensin II / Q000235:genetics; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000473:pathology*; D000067128:Extracellular Vesicles / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000473:pathology; D018919:Neovascularization, Physiologic; D020286:Pericytes / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D012171:Retinal Vessels / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics
C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D000804:Angiotensin II
Angiogenesis; Diabetic retinopathy; Extracellular vesicles; Mesenchymal stem cells; Pericytes; miR-126