Induction of pulmonary hypertensive changes by extracellular vesicles from monocrotaline-treated mice
Induction of pulmonary hypertensive changes by extracellular vesicles from monocrotaline-treated mice
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DOI：
10.1093/cvr/cvt184
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发表时间：
2013-12-01
影响因子：
10.8
通讯作者：
Klinger, James R.
中科院分区：
文献类型：
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作者：
Aliotta, Jason M.;Pereira, Mandy;Klinger, James R.
循环内皮源性细胞外囊泡（EV）水平在肺动脉高压（PAH）中发生改变，但它们是细胞损伤的生物标志物还是疾病发病机制的参与者尚不清楚。此前，我们发现肺源性ev （LEVs）诱导骨髓源性祖细胞表达肺特异性mRNA和蛋白。在这项研究中，我们试图确定LEV或血浆源性EV （PEV）是否会改变肺血管内皮细胞或骨髓祖细胞表型，从而诱导肺血管重构。将从单藜碱（MCT-EV）或载药处理小鼠（vehicle-EV）中分离的LEV、PEV注射到健康小鼠体内。通过右心室/体重（RV/BW）和血管壁厚/直径（WT/D）比评估右心室（RV）肥厚和肺血管重构。MCT组小鼠的RV/BW、WT/D比值升高（1.99 0.09 vs 1.04 0.09 mg/g; 0.159 0.002 vs 0.062 0.009）。MCT-EV注射小鼠的RV/BW、WT/D比高于vehicle-EV注射小鼠（1.63 0.09 vs 1.08 0.09 mg/g; 0.113 0.02 vs 0.056 0.01）。MCT-EV培养的骨髓细胞和MCT-EV注入小鼠的骨髓细胞中内皮祖细胞mrna和PAH中异常表达的mrna的表达高于用vehicle-EV孵育的细胞或从vehicle-EV注入小鼠中分离的细胞。MCT-EV在小鼠肺内皮细胞和与MCT-EV孵育的谱系耗尽骨髓细胞中诱导抗凋亡表型，当注射到健康小鼠时诱导肺动脉高压。mct损伤小鼠的EV参与mct诱导的肺动脉高压的发展。这种作用可能是由EV对肺血管的作用或骨髓细胞向内皮祖细胞的分化介导的，内皮祖细胞诱导肺血管重构。
Circulating endothelium-derived extracellular vesicles (EV) levels are altered in pulmonary arterial hypertension (PAH) but whether they are biomarkers of cellular injury or participants in disease pathogenesis is unknown. Previously, we found that lung-derived EVs (LEVs) induce bone marrow-derived progenitor cells to express lung-specific mRNA and protein. In this study, we sought to determine whether LEV or plasma-derived EV (PEV) alter pulmonary vascular endothelial or marrow progenitor cell phenotype to induce pulmonary vascular remodelling.LEV, PEV isolated from monocrotaline (MCT-EV)- or vehicle-treated mice (vehicle-EV) were injected into healthy mice. Right ventricular (RV) hypertrophy and pulmonary vascular remodelling were assessed by RV-to-body weight (RV/BW) and blood vessel wall thickness-to-diameter (WT/D) ratios. RV/BW, WT/D ratios were elevated in MCT- vs. vehicle-injected mice (1.99 0.09 vs. 1.04 0.09 mg/g; 0.159 0.002 vs. 0.062 0.009). RV/BW, WT/D ratios were higher in mice injected with MCT-EV vs. mice injected with vehicle-EV (1.63 0.09 vs. 1.08 0.09 mg/g; 0.113 0.02 vs. 0.056 0.01). Lineage-depleted bone marrow cells incubated with MCT-EV and marrow cells isolated from mice infused with MCT-EV had greater expression of endothelial progenitor cell mRNAs and mRNAs abnormally expressed in PAH than cells incubated with vehicle-EV or isolated from vehicle-EV infused mice. MCT-EV induced an apoptosis-resistant phenotype in murine pulmonary endothelial cells and lineage-depleted bone marrow cells incubated with MCT-EV induced pulmonary hypertension when injected into healthy mice.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.