Endothelium-derived microparticles from chronically thromboembolic pulmonary hypertensive patients facilitate endothelial angiogenesis

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Abstract

Background

Increased circulating levels of endoglin ⁺ endothelial microparticles (EMPs) have been identified in several cardiovascular disorders, related to severity. Endoglin is an auxilary receptor for transforming growth factor β (TGF-β) important in the regulation of vascular structure.

Results

We quantified the number of microparticles in plasma of six patients with chronic thromboembolic pulmonary hypertension (CTEPH) and age- and sex-matched pulmonary embolic (PE) and healthy controls and investigated the role of microparticle endoglin in the regulation of pulmonary endothelial function in vitro. Results show significantly increased levels of endoglin ⁺ EMPs in CTEPH plasma, compared to healthy and disease controls. Co-culture of human pulmonary endothelial cells with CTEPH microparticles increased intracellular levels of endoglin and enhanced TGF-β-induced angiogenesis and Smad1,5,8 phosphorylation in cells, without affecting BMPRII expression. In an in vitro model, we generated endothelium-derived MPs with enforced membrane localization of endoglin. Co-culture of these MPs with endothelial cells increased cellular endoglin content, improved cell survival and stimulated angiogenesis in a manner similar to the effects induced by overexpressed protein.

Conclusions

Increased generation of endoglin ⁺ EMPs in CTEPH is likely to represent a protective mechanism supporting endothelial cell survival and angiogenesis, set to counteract the effects of vascular occlusion and endothelial damage.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-016-0224-9) contains supplementary material, which is available to authorized users.

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Most cited references 34

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Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro.

Christian Weber, Mihail Hristov, Stefan Linder … (2004)

Endothelial progenitor cells (EPCs) play a role in the repair of ischemic or injured tissue. Because endothelial injury can be associated with apoptosis, we have investigated whether apoptotic bodies from mature endothelial cells (ECs) may affect growth and differentiation of EPCs in vitro. A 24-hour incubation of isolated human EPCs with apoptotic bodies-rich medium (ABRM) from ECs led to a significant increase in the number of spindle-shaped attached cells. EPCs were characterized by DiI-Ac-LDL/lectin staining and measurement of CD34 and kinase insert domain receptor (KDR) expression. The treatment with ABRM resulted in a 2-fold increase of DiI-Ac-LDL/lectin-positive cells and up-regulation of CD34 (22% +/- 2% versus 13% +/- 3%, P < .05 and KDR (49% +/- 12% versus 19% +/- 7%, P < .05). Fluorescence and confocal laser microscopy demonstrated the uptake of apoptotic bodies by the EPCs. Apoptotic bodies-depleted medium had no effect, whereas the incubation with suspension of apoptotic bodies induced effects similar to those of ABRM. Our results suggest that apoptotic bodies from ECs are taken up by EPCs, increasing their number and differentiation state. Such a mechanism may facilitate the repair of injured endothelium and may represent a new signaling pathway between progenitor and damaged somatic cells.

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TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex.

C Dumont, Armelle Regnault, Nicolas Blanchard-Gutton … (2002)

We show in this study that human T cells purified from peripheral blood, T cell clones, and Jurkat T cells release microvesicles in the culture medium. These microvesicles have a diameter of 50-100 nm, are delimited by a lipidic bilayer membrane, and bear TCR beta, CD3epsilon, and zeta. This microvesicle production is regulated because it is highly increased upon TCR activation, whereas another mitogenic signal, such as PMA and ionomycin, does not induce any release. T cell-derived microvesicles also contain the tetraspan protein CD63, suggesting that they originate from endocytic compartments. They contain adhesion molecules such as CD2 and LFA-1, MHC class I and class II, and the chemokine receptor CXCR4. These transmembrane proteins are selectively sorted in microvesicles because CD28 and CD45, which are highly expressed at the plasma membrane, are not found. The presence of phosphorylated zeta in these microvesicles suggests that the CD3/TCR found in the microvesicles come from the pool of complexes that have been activated. Proteins of the transduction machinery, tyrosine kinases of the Src family, and c-Cbl are also observed in the T cell-derived microvesicles. Our data demonstrate that T lymphocytes produce, upon TCR triggering, vesicles whose morphology and phenotype are reminiscent of vesicles of endocytic origin produced by many cell types and called exosomes. Although the exact content of T cell-derived exosomes remains to be determined, we suggest that the presence of TCR/CD3 at their surface makes them powerful vehicles to specifically deliver signals to cells bearing the right combination of peptide/MHC complexes.

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Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery.

Susan van Dommelen, Pieter Vader, Samira Lakhal … (2012)

Cell-derived membrane vesicles (CMVs) are endogenous carriers transporting proteins and nucleic acids between cells. They appear to play an important role in many disease processes, most notably inflammation and cancer, where their efficient functional delivery of biological cargo seems to contribute to the disease progress. CMVs encompass a variety of submicron vesicular structures that include exosomes and shedding vesicles. The lipids, proteins, mRNA and microRNA (miRNA) delivered by these vesicles change the phenotype of the receiving cells. CMVs have created excitement in the drug delivery field, because they appear to have multiple advantages over current artificial drug delivery systems. Two approaches to exploit CMVs for delivery of exogenous therapeutic cargoes in vivo are currently considered. One approach is based on engineering of natural CMVs in order to target certain cell types using CMVs loaded with therapeutic compounds. In the second approach, essential characteristics of CMVs are being used to design nano-scaled drug delivery systems. Although a number of limiting factors in the clinical translation of the exciting research findings so far exist, both approaches are promising for the development of a potentially novel generation of drug carriers based on CMVs. Copyright © 2011 Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Beata Wojciak-Stothard:

ORCID: http://orcid.org/0000-0002-6607-7372

0207 594 6821 , b.wojciak-stothard@imperial.ac.uk

Journal

Journal ID (nlm-ta): J Biomed Sci

Journal ID (iso-abbrev): J. Biomed. Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central (London )

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date (Electronic): 19 January 2016

Publication date PMC-release: 19 January 2016

Publication date Collection: 2016

Volume: 23

Electronic Location Identifier: 4

Affiliations

[ ]Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, London, UK

[ ]National Pulmonary Hypertension Service, Imperial College Healthcare NHS Trust, London, UK

[ ]Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain

Author information

Beata Wojciak-Stothard http://orcid.org/0000-0002-6607-7372

Article

Publisher ID: 224

DOI: 10.1186/s12929-016-0224-9

PMC ID: 4717540

PubMed ID: 26786759

SO-VID: 8754bd53-2518-4319-b6a7-cec01d83e062

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 14 August 2015

Date accepted : 11 January 2016

Funding

Funded by: Ministerio de Economia y Competitividad of Spain

Award ID: SAF2013-43421-R to CB

Award Recipient : Carmelo Bernabeu

Funded by: FundRef http://dx.doi.org/10.13039/501100000274, British Heart Foundation (GB);

Award ID: 11/13/28765

Award Recipient : Beata Wojciak-Stothard

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: endoglin,angiogenesis,pulmonary hypertension,microparticles

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ScienceOpen disciplines: Molecular medicine

Keywords: endoglin, angiogenesis, pulmonary hypertension, microparticles

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Endothelium-derived microparticles from chronically thromboembolic pulmonary hypertensive patients facilitate endothelial angiogenesis

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Abstract

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Most cited references 34

Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro.

TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex.

Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery.

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