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      Extracellular Endothelial Cell-Derived Vesicles: Emerging Role in Cardiac and Vascular Remodeling in Heart Failure

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          Abstract

          Extracellular vesicles play a pivotal role in numerous physiological (immune response, cell-to-cell cooperation, angiogenesis) and pathological (reparation, inflammation, thrombosis/coagulation, atherosclerosis, endothelial dysfunction) processes. The development of heart failure is strongly associated with endothelial dysfunction, microvascular inflammation, alteration in tissue repair, and cardiac and vascular remodeling. It has been postulated that activated endothelial cell-derived vesicles are not just transfer forms of several active molecules (such as regulatory peptides, coagulation factors, growth factors, active molecules, hormones that are embedded onto angiogenesis, tissue reparation, proliferation, and even prevention from ischemia/hypoxia), but are instead involved in direct myocardial and vascular damage due to regulation of epigenetic responses of the tissue. These responses are controlled by several factors, such as micro-RNAs, that are transferred inside extracellular vesicles from mother cells to acceptor cells and are transductors of epigenetic signals. Finally, it is not a uniform opinion whether different phenotypes of heart failure are the result of altered cardiac and vascular reparation due to certain epigenetic responses, which are yielded by co-morbidities, such as diabetes mellitus and obesity. The aim of the review is to summarize knowledge regarding the role of various types of extracellular endothelial cell-derived vesicles in the regulation of cardiac and vascular remodeling in heart failure.

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          Most cited references103

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          Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.

          Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.
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            Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis.

            The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.
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              Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease

              Fibroblasts comprise the largest cell population in the myocardium. In heart disease, the number of fibroblasts is increased either by replication of the resident myocardial fibroblasts, migration and transformation of circulating bone marrow cells, or by transformation of endothelial/epithelial cells into fibroblasts and myofibroblasts. The primary function of fibroblasts is to produce structural proteins that comprise the extracellular matrix (ECM). This can be a constructive process; however, hyperactivity of cardiac fibroblasts can result in excess production and deposition of ECM proteins in the myocardium, known as fibrosis, with adverse effects on cardiac structure and function. In addition to being the primary source of ECM proteins, fibroblasts produce a number of cytokines, peptides, and enzymes among which matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), directly impact the ECM turnover and homeostasis. Function of fibroblasts can also in turn be regulated by MMPs and TIMPs. In this review article, we will focus on the function of cardiac fibroblasts in the context of ECM formation, homeostasis and remodeling in the heart. We will discuss the origins and multiple roles of cardiac fibroblasts in myocardial remodeling in different types of heart disease in patients and in animal models. We will further provide an overview of what we have learned from experimental animal models and genetically modified mice with altered expression of ECM regulatory proteins, MMPs and TIMPs.
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                Author and article information

                Contributors
                Journal
                Front Cardiovasc Med
                Front Cardiovasc Med
                Front. Cardiovasc. Med.
                Frontiers in Cardiovascular Medicine
                Frontiers Media S.A.
                2297-055X
                15 April 2020
                2020
                : 7
                : 47
                Affiliations
                [1] 1Internal Medicine Department, State Medical University, Ministry of Health of Ukraine , Zaporozhye, Ukraine
                [2] 2Internal Medicine Department, Medical Academy of Post-graduate Education, Ministry of Health of Ukraine , Zaporozhye, Ukraine
                Author notes

                Edited by: Susumu Minamisawa, Jikei University School of Medicine, Japan

                Reviewed by: Andrea Caporali, University of Edinburgh, United Kingdom; Tetsuo Sasano, Tokyo Medical and Dental University, Japan

                *Correspondence: Alexander E. Berezin aeberezin@ 123456gmail.com

                This article was submitted to Heart Failure and Transplantation, a section of the journal Frontiers in Cardiovascular Medicine

                †ORCID: Alexander E. Berezin orcid.org/0000-0002-0446-3999

                Article
                10.3389/fcvm.2020.00047
                7174683
                32351973
                d4f3f620-c99a-4fb2-9097-febdeee9a729
                Copyright © 2020 Berezin and Berezin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 11 December 2019
                : 10 March 2020
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 144, Pages: 14, Words: 10212
                Categories
                Cardiovascular Medicine
                Review

                extracellular vesicles,cardiac and vascular remodeling,heart failure,epigenetics,co-morbidities

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