Induction of pulmonary hypertensive changes by extracellular vesicles from monocrotaline-treated mice

Aliotta, Jason M.; Pereira, Mandy; Amaral, Ashley; Sorokina, Arina; Igbinoba, Zenas; Hasslinger, Alexander; El-Bizri, R.; Rounds, Sharon; Quesenberry, Peter J.; Klinger, James R.

doi:10.1093/cvr/cvt184

Cited by 65 publications

(60 citation statements)

References 24 publications

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“…[7][8][9] EVs released by MSCs were shown to express proteins involved in MSC self-renewal and differentiation capability. 10 Moreover, analysis of the nucleic acid composition showed the presence of MSC-specific mRNA and mature microRNAs (miRNAs).…”

mentioning

confidence: 99%

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Collino

Bruno²,

Incarnato

et al. 2015

Journal of the American Society of Nephrology

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222

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Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cellpromoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.

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mentioning

confidence: 99%

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Collino

Bruno²,

Incarnato

et al. 2015

Journal of the American Society of Nephrology

Self Cite

222

227

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“…Microparticles have been investigated in animal models of PAH [107][108][109]. The results support the hypothesis that microparticles might act directly on endothelial function by altering vascular balance, through a reduction of nitric oxide production, an increase in oxidative stress and as a circulating source of vasoconstrictor agents such as thromboxane A 2 .…”

Section: Pulmonary Arterial Hypertensionmentioning

confidence: 57%

Cell-derived microparticles and the lung

et al. 2016

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Cell-derived microparticles are small (0.1-1 μm) vesicles shed by most eukaryotic cells upon activation or during apoptosis. Microparticles carry on their surface, and enclose within their cytoplasm, molecules derived from the parental cell, including proteins, DNA, RNA, microRNA and phospholipids. Microparticles are now considered functional units that represent a disseminated storage pool of bioactive effectors and participate both in the maintenance of homeostasis and in the pathogenesis of diseases. The mechanisms involved in microparticle generation include intracellular calcium mobilisation, cytoskeleton rearrangement, kinase phosphorylation and activation of the nuclear factor-κB. The role of microparticles in blood coagulation and inflammation, including airway inflammation, is well established in in vitro and animal models. The role of microparticles in human pulmonary diseases, both as pathogenic determinants and biomarkers, is being actively investigated. Microparticles of endothelial origin, suggestive of apoptosis, have been demonstrated in the peripheral blood of patients with emphysema, lending support to the hypothesis that endothelial dysfunction and apoptosis are involved in the pathogenesis of the disease and represent a link with cardiovascular comorbidities. Microparticles also have potential roles in patients with asthma, diffuse parenchymal lung disease, thromboembolism, lung cancer and pulmonary arterial hypertension. @ERSpublications Microparticles are potential biomarkers and targets for therapeutic interventions in respiratory medicine http://ow.ly/ZTCp6

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“…Currently, they are divided into three classes primarily on the basis of their (126) showed that circulating MPs from hypoxic rats can suppress endothelial-dependent vascular relaxation in rat aorta and pulmonary arteries by decreasing NO production (c). More recently, Aliotta and colleagues (127) reported that healthy mice injected with circulating or lung EVs isolated from monocrotaline-treated mice show elevated right ventricular-to-body weight ratio and pulmonary arterial wall thickness-to-diameter ratio, compared with that of mice injected with control EVs (d). Deng and colleagues (130) showed a high abundance of microRNA (miR)-143-3p in pulmonary arterial smooth muscle cell (PASMC)-derived exosomes and a paracrine promigratory and proangiogenic effect of these miR-143-3p-enriched PASMC-derived exosomes on pulmonary arterial endothelial cell (e).…”

Section: Signaling Through Evsmentioning

confidence: 99%

“…Higher levels of endothelium-derived MPs bearing E-selectin are also noted in patients with thromboembolic PH as compared with subjects with nonthromboembolic PH (125), suggesting that the cause of the disease may influence MP levels (17). MPs are not only a biomarker of PH; they also actively contribute to the development of PH (126,127). Visovatti and colleagues demonstrated increased CD39 expression and function in the circulating MPs of patients with idiopathic PAH, which may be associated with the increased ATPase/ADPase activity in MPs (128).…”

Section: Signaling Through Evsmentioning

confidence: 99%

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Gao

Chen

Raj

2016

Am J Respir Cell Mol Biol

119

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In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, other mechanisms exist by which there is cross-talk between these two cell types, including communication via the myoendothelial injunctions and information transfer via extracellular vesicles. Emerging evidence suggests that these nonparacrine mechanisms play an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension.Keywords: paracrine; myoendothelial injunction; microvesicles; vasoconstriction; vascular remodelingIn the pulmonary vasculature, endothelial cells (ECs) and smooth muscle cells (SMCs) are the key cell types involved in the regulation of vessel diameter in most of the pulmonary vascular tree and thereby they regulate pulmonary arterial pressure and total vascular resistance. ECs, which are strategically located as the innermost layer of the blood vessel and are in contact with the circulating blood, exert a delicate and constant influence on the underlying vascular smooth muscle cells (VSMCs). It is well recognized that the regulation of pulmonary vasoreactivity by the endothelium is predominantly accomplished by paracrine signaling through the release of various vasoactive agents such as nitric oxide (NO), endothelin-1 (ET-1) (1-3), and others (4-8). However, there is increasing evidence that the relationship between the EC and the SMC is not a simple one-way interaction from the endothelium to the SMC; rather, there are complicated interactions between them (9-11). Moreover, the communication patterns are not limited to paracrine signaling; cross-talk through myoendothelial gap junctions (MEJs), extracellular vesicles (EVs), and other mechanisms is critically involved (12)(13)(14)(15)(16)(17)(18)(19)(20). These mechanisms operate in a complicated but co-ordinated manner to maintain the homeostasis of the pulmonary circulation. Under pathological conditions, the interaction between ECs and VSMCs may be chronically altered so that a sustained increase in vasocontractility and abnormal vascular proliferation develops, which leads to high pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and the clinical condition, pulmonary hypertension (PH) (1,(21)(22)(23)(24). This article discusses the recent progress in our knowledge of the interactions between ECs and SMCs thr...

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Induction of pulmonary hypertensive changes by extracellular vesicles from monocrotaline-treated mice

Abstract: EV from MCT-injured mice contribute to the development of MCT-induced pulmonary hypertension. This effect may be mediated directly by EV on the pulmonary vasculature or by differentiation of bone marrow cells to endothelial progenitor cells that induce pulmonary vascular remodelling.

Cited by 65 publications

References 24 publications

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Cell-derived microparticles and the lung

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

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