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Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

ABSTRACT: As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density, and preserved cardiac ejection fraction. We were able to maximally rescue microvascular and cardiac function with very low doses of antagomir, which specifically silences miR-200c-3p expression in non-myocyte cells. Our results reveal vesicle transfer of miR-200c-3p from cardiomyocytes to cardiac endothelial cells, underlining the importance of cardiac intercellular communication in the pathophysiology of heart failure.

SUBMITTER: Ottaviani L

PROVIDER: S-EPMC9171264 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

Ottaviani Lara L Juni Rio P RP de Abreu Ricardo C RC Sansonetti Marida M Sampaio-Pinto Vasco V Halkein Julie J Hegenbarth Jana C JC Ring Nadja N Knoops Kevin K Kocken Jordy M M JMM Jesus Carlos de C Ernault Auriane C AC El Azzouzi Hamid H Rühle Frank F Olieslagers Servé S Fernandes Hugo H Ferreira Lino L Braga Luca L Stoll Monika M Nascimento Diana S DS de Windt Leon J LJ da Costa Martins Paula A PA

Molecular therapy : the journal of the American Society of Gene Therapy 20220309 6

As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic ...[more]

PMID: 35278675

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Project description:BackgroundPremature infants requiring mechanical ventilation and supplemental oxygen for respiratory support are at increased risk for bronchopulmonary dysplasia (BPD), wherein inflammation have been proposed as a driver of hyperoxia-induced injuries, including persistent loss of endothelial progenitor cells (EPCs), impaired vascularization and eventual alveolar simplification in BPD lungs. However, the underlying mechanisms linking these phenomena remain poorly defined.MethodsWe used clodronate liposomes to deplete macrophages in a mouse model of neonatal hyperoxia-induced lung injury to evaluate if EPC loss in BPD lungs could be an effect of macrophage infiltration. We further generated in vitro culture systems initiated with cord blood (CB)-derived CD34+ EPCs and neonatal macrophages either polarized from CB-derived monocytes or isolated from tracheal aspirates of human preterm infants requiring mechanical ventilation and oxygen supplementation, to identify EV-transmitted molecular mechanism that is critical for inhibitory actions of hyperoxic macrophages on EPCs.ResultsInitial experiments using mouse model identified the crucial role of macrophage infiltration in eliciting significant reduction of c-Kit+ EPCs in BPD lungs. Further examination of this concept in human system, we found that hyperoxia-exposed neonatal macrophages hamper human CD34+ EPC maintenance and impair endothelial function in the differentiated progeny via the EV transmission of miR-23a-3p. Notably, treatment with antagomiR-23a-3p to silence miR-23a-3p in vivo enhances c-Kit+ EPC maintenance, and increases capillary density, and consequently mitigates simplified alveolarization in BPD lungs.ConclusionOur findings highlight the importance of pulmonary intercellular communication in the pathophysiology of BPD, by identifying a linkage through vesicle transfer of miR-23a-3p from hyperoxic macrophages to EPCs, and thus demonstrating potential for novel therapeutic target in BPD.

Dataset Information

Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

Publications

Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

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