Teresa M Ribeiro-Rodrigues1,2, Tiago L Laundos3,4,5, Rita Pereira-Carvalho1,2, Daniela Batista-Almeida1,2, Ricardo Pereira1,2, Vanessa Coelho-Santos1,2,6, Ana P Silva1,2,6, Rosa Fernandes1,2, Monica Zuzarte1,2, Francisco J Enguita7, Marina C Costa7, Perpetua Pinto-do-Ó3,4,5, Marta T Pinto3,8, Pedro Gouveia2,9, Lino Ferreira2,9, Justin C Mason10, Paulo Pereira1,2,11, Brenda R Kwak12, Diana S Nascimento3,4, Henrique Girão1,2. 1. Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal. 2. CNC.IBILI, University of Coimbra, Portugal. 3. Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal. 4. INEB-Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal. 5. Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal. 6. Institute of Pharmacology and Experimental Therapeutics, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal. 7. Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisboa, Portugal. 8. Institute of Molecular Pathology and Immunology (Ipatimup), University of Porto, Portugal. 9. CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal. 10. Vascular Sciences Unit, Imperial Centre for Translational & Experimental Medicine, Imperial College London, London, UK. 11. CEDOC, NOVA Medical School, NOVA University of Lisbon, Lisboa 1169-056, Portugal. 12. Department of Pathology and Immunology, and Department of Medical Specialties-Cardiology, University of Geneva, CH-1211 Geneva, Switzerland.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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