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Molecular mechanisms of extracellular vesicle-induced vessel destabilization in diabetic retinopathy

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Abstract

Aims

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.

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Acknowledgments

The authors are grateful to Dr. Serena Grimaldi for technical help and Prof. Giovanni Camussi for help and advice.

Funding

This study was funded by an European Foundation for the Study of Diabetes/Novartis award.

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Author notes

    Authors and Affiliations

    1. Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy

      Aurora Mazzeo, Elena Beltramo, Alessandra Iavello, Andrea Carpanetto & Massimo Porta

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    1. Aurora Mazzeo
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    2. Elena Beltramo
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    3. Alessandra Iavello
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    4. Andrea Carpanetto
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    5. Massimo Porta
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    Correspondence to Elena Beltramo.

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    Conflict of interest

    Aurora Mazzeo, Elena Beltramo, Alessandra Iavello, Andrea Carpanetto and Massimo Porta declare that they have no conflicts of interest.

    Statement of human and animal rights

    This article does not contain any studies with human or animal subjects performed by the any of the authors.

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    For this type of study formal consent is not required.

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    Managed by Massimo Federici.

    A. Mazzeo and E. Beltramo contributed equally to this work.

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    Mazzeo, A., Beltramo, E., Iavello, A. et al. Molecular mechanisms of extracellular vesicle-induced vessel destabilization in diabetic retinopathy. Acta Diabetol 52, 1113–1119 (2015). https://doi.org/10.1007/s00592-015-0798-9

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    • DOI: https://doi.org/10.1007/s00592-015-0798-9

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