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      Role of Extracellular Vesicles and microRNAs on Dysfunctional Angiogenesis during Preeclamptic Pregnancies

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          Abstract

          Preeclampsia is a syndrome characterized by hypertension during pregnancy, which is a leading cause of morbidity and mortality in both mother and newborn in developing countries. Some advances have increased the understanding of pathophysiology of this disease. For example, reduced utero-placental blood flow associated with impaired trophoblast invasion may lead to a hypoxic placenta that releases harmful materials into the maternal and feto-placental circulation and impairs endothelial function. Identification of these harmful materials is one of the hot topics in the literature, since these provide potential biomarkers. Certainty, such knowledge will help us to understand the miscommunication between mother and fetus. In this review we highlight how placental extracellular vesicles and their cargo, such as small RNAs (i.e., microRNAs), might be involved in endothelial dysfunction, and then in the angiogenesis process, during preeclampsia. Currently only a few reports have addressed the potential role of endothelial regulatory miRNA in the impaired angiogenesis in preeclampsia. One of the main limitations in this area is the variability of the analyses performed in the current literature. This includes variability in the size of the particles analyzed, and broad variation in the exosomes considered. The quantity of microRNA targets genes suggest that practically all endothelial cell metabolic functions might be impaired. More studies are required to investigate mechanisms underlying miRNA released from placenta upon endothelial function involved in the angiogenenic process.

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          Most cited references138

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          Biological properties of extracellular vesicles and their physiological functions

          In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
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            Biogenesis and secretion of exosomes.

            Although observed for several decades, the release of membrane-enclosed vesicles by cells into their surrounding environment has been the subject of increasing interest in the past few years, which led to the creation, in 2012, of a scientific society dedicated to the subject: the International Society for Extracellular Vesicles. Convincing evidence that vesicles allow exchange of complex information fuelled this rise in interest. But it has also become clear that different types of secreted vesicles co-exist, with different intracellular origins and modes of formation, and thus probably different compositions and functions. Exosomes are one sub-type of secreted vesicles. They form inside eukaryotic cells in multivesicular compartments, and are secreted when these compartments fuse with the plasma membrane. Interestingly, different families of molecules have been shown to allow intracellular formation of exosomes and their subsequent secretion, which suggests that even among exosomes different sub-types exist. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              miR-126 regulates angiogenic signaling and vascular integrity.

              Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                18 March 2016
                2016
                : 7
                : 98
                Affiliations
                [1] 1Group of Investigation in Tumor Angiogenesis, Vascular Physiology Laboratory, Universidad del Bío-Bío Chillán, Chile
                [2] 2Group of Research and Innovation in Vascular Health, Department of Basic Sciences, Universidad del Bío-Bío Chillán, Chile
                [3] 3Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción Concepción, Chile
                [4] 4Departments of Obstetrics, Gynecology and Reproductive Sciences, Epidemiology, and the Clinical and Translational Science Institute, Magee-Womens Research Institute, University of Pittsburgh Pittsburgh, PA, USA
                [5] 5Exosome Biology Laboratory, Faculty of Medicine and Biomedical Sciences, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, The University of Queensland Brisbane, QLD, Australia
                [6] 6Ochsner Clinic Foundation, Maternal-Fetal Medicine, Department of Obstetrics and Gynecology New Orleans, LA, USA
                Author notes

                Edited by: Michael A. Hill, University of Missouri, USA

                Reviewed by: Jianbo Wu, University of Missouri, USA; Brett M. Mitchell, Texas A&M Health Science Center, USA

                *Correspondence: Carlos A. Escudero cescudero@ 123456ubiobio.cl

                This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2016.00098
                4796029
                27047385
                037debcb-8118-48ec-8d83-00c5f0108077
                Copyright © 2016 Escudero, Herlitz, Troncoso, Acurio, Aguayo, Roberts, Truong, Duncombe, Rice and Salomon.

                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) or licensor 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
                : 10 December 2015
                : 01 March 2016
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 183, Pages: 17, Words: 13873
                Funding
                Funded by: Fondo Nacional de Desarrollo Científico y Tecnológico 10.13039/501100002850
                Categories
                Physiology
                Review

                Anatomy & Physiology
                preeclampsia,exosomes,micrornas,endothelial dysfunction
                Anatomy & Physiology
                preeclampsia, exosomes, micrornas, endothelial dysfunction

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