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MircoRNA in Extracellular Vesicles from Patients with Pulmonary Arterial Hypertension Alters Endothelial Angiogenic Response.

ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by a progressive elevation of pulmonary pressure leading to right ventricular dysfunction and is associated with a poor prognosis. Patients with PAH have increased numbers of circulating extracellular vesicles (EVs) and altered expression of circulating microRNAs (miRs). The study aimed to evaluate the miR profile contained within purified EVs derived from the plasma of PAH patients as compared to healthy controls (HC). Circulating EVs, purified from platelet-free plasma were analyzed using flow cytometry, western blot, and electron microscopy. Total RNA isolated from EVs was subjected to Microarray analysis using GeneChip miRNA 4.0 Array and bioinformatics tools. Overexpression and inhibition of miRs were conducted in human pulmonary artery endothelial cells (hPAECs) that had been incubated previously with either PAH- or HC-derived EVs. Cell proliferation (MTT assay) and angiogenesis (tube formation assay) were tested in hPAECs to determine miR functionality. MiR profiling revealed 370 heats while comparing PAH and HC groups, 22 of which were found to be down-regulated and 6 were up-regulated in the PAH EVs. Among the altered miRs, miR-486-5p was overexpressed, while miR-26a-5p was downregulated in PAH EVs compared to HC EVs. Inhibition of mir-486-5p or overexpression of miR-26a-5p in hPAECs post-exposure of PAH EVs abrogated proangiogenic and proliferative effects posed by PAH EVs contrary to HC EVs. The angiogenic and proliferative effects of the miRs from PAH EVs were observed to be mediated through nuclear factor (NF)-κB activation. PAH EVs carry and present an altered miR profile that can be targeted to restrict angiogenesis and reduce pulmonary endothelium activation. Further studies concerning miRs from circulating heterogeneous EVs in PAH patients are warranted to understand their potential as targets for treatment in PAH.

SUBMITTER: Khandagale A

PROVIDER: S-EPMC9570422 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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MircoRNA in Extracellular Vesicles from Patients with Pulmonary Arterial Hypertension Alters Endothelial Angiogenic Response.

Khandagale Avinash A Corcoran Padraic P Nikpour Maryam M Isaksson Anders A Wikström Gerhard G Siegbahn Agneta A Christersson Christina C

International journal of molecular sciences 20221008 19

Pulmonary arterial hypertension (PAH) is characterized by a progressive elevation of pulmonary pressure leading to right ventricular dysfunction and is associated with a poor prognosis. Patients with PAH have increased numbers of circulating extracellular vesicles (EVs) and altered expression of circulating microRNAs (miRs). The study aimed to evaluate the miR profile contained within purified EVs derived from the plasma of PAH patients as compared to healthy controls (HC). Circulating EVs, puri ...[more]

PMID: 36233263

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Project description:Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair. However, local or distant cues may prevent effective revascularization. Extracellular vesicles (EV) are produced by all cells and endothelium is a rich source of EVs that have access to the main circulation thereby potentially impacting local and distant tissue function. Systemic inflammation associated with conditions such as obesity as well as the acute inflammatory response elicited by a cardiac event can significantly increase the EV release by endothelium and alter their miRNA, protein or lipid cargo. Our laboratory has previously shown that EVs released by adipose tissue endothelial cells exposed to chronic inflammation have angiostatic effects on naïve adipose tissue EC in vitro. Whether the observed effect is specific to EVs from adipose tissue endothelium or is a more general feature of the endothelial EVs exposed to pro-inflammatory cues is currently unclear. The objective of this study was to investigate the angiostatic effects of EVs produced by EC from the coronary artery and adipose microvasculature exposed to pro-inflammatory cytokines (PIC) on naïve coronary artery EC. We have found that EVs from both EC sources have angiostatic effects on the coronary endothelium. EVs produced by cells in a pro-inflammatory environment reduced proliferation and barrier function of EC without impacting cellular senescence. Some of these functional effects could be attributed to the miRNA cargo of EVs. Several miRNAs such as miR-451, let-7, or miR-23a impact on multiple pathways responsible for proliferation, cellular permeability and angiogenesis. Collectively, our data suggests that EVs may compete with pro-angiogenic cues in the ischemic myocardium therefore slowing down the repair response. Acute treatments with inhibitors that prevent endogenous EV release immediately after an ischemic event may contribute to better efficacy of therapeutic approaches using functionalized exogenous EVs or other pro-angiogenic approaches.

Project description:Introduction: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are severe complications of patients with systemic sclerosis (SSc). Currently, there are a few tests for early identification of these conditions, although they are invasive and time-consuming. Extracellular vesicles (EVs) offer a promising possibility for gathering information on tissue health. This study aims to characterize EVs in cases of systemic sclerosis complicated by pulmonary hypertension and pulmonary fibrosis. Methods: A cohort of 58 patients with SSc was evaluated, including 14 with pulmonary hypertension, 17 with pulmonary fibrosis, and 27 without complications. Additionally, 11 healthy subjects, matched for sex and age, served as a control group. EVs were characterized by using a MACSplex kit to analyze the expression of 37 membrane markers. Results: After the overall analysis, we show that EVs from SSc patients had higher expression of CD146, CD42a, and CD29 (p = 0.03, p = 0.02 and p = 0.05) but lower expression of HLA-ABC with respect to the control patients (p = 0.02). Multivariate analyses demonstrated that only CD42a has a significant association with the disease (p = 0.0478). In group comparative analyses (PAH, ILD, uncomplicated systemic sclerosis (named SSc no PAH no ILD), and controls), CD3 and CD56 were higher in PAH patients, with respect to the controls, ILD, and the group SSc no PAH no ILD (CD3: p = 0.01, p = 0.003, p = 0.0005; CD56: p = 0.002, p < 0.0001, p = 0.0002). HLA-DR showed higher expression in PAH patients with respect to ILD patients (p = 0.02), CD25 showed higher expression in PAH patients with respect uncomplicated SSc (p = 0.02), and CD42a showed higher expression in PAH patients with respect to the controls (p = 0.03); nevertheless, multivariate analyses demonstrated that only CD3 retained its association with PAH. Conclusions: The expression of CD42a, a platelet-derived marker indicating endothelial damage, suggests its potential to provide information on the state of the microcirculation in systemic sclerosis. The higher expression of CD3 on the surface of the EVs in PAH patients might indicate increased T-cell activity in tissues, with a possible association with the development of pulmonary hypertension.

Project description:IntroductionPulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE) with increased mortality. A prothrombotic state may contribute to pathogenesis of SLE-PAH. Extracellular vesicles (EVs) are known to be associated with thrombosis. Here, we investigated circulating EVs and their associations with SLE-PAH.MethodsEighteen SLE-PAH patients, 36 SLE-non-PAH patients, and 36 healthy controls (HCs) were enrolled. Flow cytometry was used to analyze circulating EVs from leukocytes (LEVs), red blood cells (REVs), platelets (PEVs), endothelial cells (EEVs), and Annexin V+ EVs with membrane phosphatidylserine (PS) exposure.ResultsPlasma levels of all EV subgroups were elevated in SLE patients with or without PAH compared to HCs. Furthermore, plasma Annexin V+ EVs, LEVs, PEVs, REVs, EEVs, and Annexin V+ REVs were significantly elevated in SLE-PAH patients compared to SLE-non-PAH patients. Additionally, PAH patients with moderate/high SLE showed a significant increase in LEVs, PEVs, REVs, Annexin V+ EVs, and Annexin V+ REVs compared to SLE-non-PAH patients. However, PAH patients with inactive/mild SLE only exhibited elevations in Annexin V+ EVs, REVs, and Annexin V+ REVs. In the SLE-PAH patients, EEVs were positively correlated with pulmonary arterial systolic pressure, while PEVs and EEVs were positively correlated with right ventricular diameter. Moreover, the receiver operating characteristic curve indicated that Annexin V+ EVs, LEVs, PEVs, REVs, EEVs and Annexin V+ REVs could predict the presence of PAH in SLE patients. Importantly, multivariate logistic regression analysis showed that circulating levels of LEVs or REVs, anti-nRNP antibody, and serositis were independent risk factors for PAH in SLE patients.DiscussionFindings reveal that specific subgroups of circulating EVs contribute to the hypercoagulation state and the severity of SLE-PAH. Higher plasma levels of LEVs or REVs may serve as biomarkers for SLE-PAH.

Dataset Information

MircoRNA in Extracellular Vesicles from Patients with Pulmonary Arterial Hypertension Alters Endothelial Angiogenic Response.

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MircoRNA in Extracellular Vesicles from Patients with Pulmonary Arterial Hypertension Alters Endothelial Angiogenic Response.

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