Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis

T.M. Ribeiro-Rodrigues, T.L. Laundos, R. Pereira-Carvalho, D. Batista-Almeida, R. Pereira, V. Coelho-Santos, A.P. Silva, R. Fernandes, M. Zuzarte, F.J. Enguita, M.C. Costa, P. Pinto-Do-O, M.T. Pinto, P. Gouveia, L. Ferreira, J.C. Mason, P. Pereira, B.R. Kwak, D.S. Nascimento, H. Girao

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Aims Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide and results from an obstruction in the blood supply to a region of the heart. In an attempt to replenish oxygen and nutrients to the deprived area, affected cells release signals to promote the development of new vessels and confer protection against MI. However, the mechanisms underlying the growth of new vessels in an ischaemic scenario remain poorly understood. Here, we show that cardiomyocytes subjected to ischaemia release exosomes that elicit an angiogenic response of endothelial cells (ECs). Methods and results Exosomes secreted by H9c2 myocardial cells and primary cardiomyocytes, cultured either in control or ischaemic conditions were isolated and added to ECs. We show that ischaemic exosomes, in comparison with control exosomes, confer protection against oxidative-induced lesion, promote proliferation, and sprouting of ECs, stimulate the formation of capillary-like structures and strengthen adhesion complexes and barrier properties. Moreover, ischaemic exosomes display higher levels of metalloproteases (MMP) and promote the secretion of MMP by ECs. We demonstrate that miR-222 and miR-143, the relatively most abundant miRs in ischaemic exosomes, partially recapitulate the angiogenic effect of exosomes. Additionally, we show that ischaemic exosomes stimulate the formation of new functional vessels in vivo using in ovo and Matrigel plug assays. Finally, we demonstrate that intramyocardial delivery of ischaemic exosomes improves neovascularization following MI. Conclusions This study establishes that exosomes secreted by cardiomyocytes under ischaemic conditions promote heart angiogenesis, which may pave the way towards the development of add-on therapies to enhance myocardial blood supply. © 2017 The Author.
Original languageEnglish
Pages (from-to)1338-1350
Number of pages13
JournalCardiovascular Research
Volume113
Issue number11
DOIs
Publication statusPublished - Sep 2017

Keywords

  • Angiogenesis
  • Coronary collateral circulation
  • Exosomes
  • Extracellular vesicles
  • Ischaemia
  • Myocardial infarction
  • matrigel
  • metalloproteinase
  • microRNA 143
  • microRNA 222
  • angiogenesis
  • animal cell
  • animal experiment
  • animal model
  • Article
  • capillary
  • cardiac muscle cell
  • cell adhesion
  • cell isolation
  • cell migration
  • cell proliferation
  • cell protection
  • cell stimulation
  • cell structure
  • cell survival
  • cellular secretion
  • chick embryo
  • controlled study
  • coronary artery collateral circulation
  • embryo
  • endothelium cell
  • exosome
  • extracellular matrix
  • fetus
  • H9c2(2-1) cell line
  • heart cell culture
  • heart ejection fraction
  • heart function
  • heart infarction
  • heart output
  • human
  • human cell
  • in vivo study
  • neovascularization (pathology)
  • nonhuman
  • oxidative stress
  • permeability barrier
  • primary cell culture
  • primary cell line
  • priority journal
  • rat
  • upregulation

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