Pulmonary arterial hypertension (PAH) refers to a set of heterogeneous vascular diseases defined by elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), leading to right ventricular (RV) remodeling and often death. Early increases in pulmonary artery stiffness in PAH drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling. Dysregulation of microRNAs can drive PAEC dysfunction. However, the role of vascular stiffness in regulating pathogenic microRNAs in PAH is incompletely understood. Here, we demonstrated that extracellular matrix (ECM) stiffening downregulated miR-7 levels in PAECs. The RNA binding protein Quaking (QKI) has been implicated in the biogenesis of miR-7. Correspondingly, we found that ECM stiffness up-regulated QKI, and QKI knockdown led to increased miR-7. Downstream of the QKI-miR-7 axis, the serine and arginine rich splicing factor 1 (SRSF1) was identified as a direct target of miR-7. Correspondingly, SRSF1 was reciprocally up-regulated in PAECs exposed to stiff ECM and was negatively correlated with miR-7. Decreased miR-7 and increased QKI and SRSF1 were observed in lungs from PAH patients and PAH rats exposed to SU5416/hypoxia. Lastly, miR-7 upregulation inhibited human PAEC migration, while forced SRSF1 expression reversed this phenotype, proving that miR-7 depended upon SRSF1 to control migration. In aggregate, these results define the QKI-miR-7-SRSF1 axis as a mechanosensitive mechanism linking pulmonary arterial vascular stiffness to pathogenic endothelial function. These findings emphasize implications relevant to PAH and suggest the potential benefit of developing therapies that target this miRNA-dependent axis in PAH.

中文翻译：

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基质硬化在肺动脉内皮细胞中诱导致病性 QKI-miR-7-SRSF1 信号轴

肺动脉高压 (PAH) 是指一组异质性血管疾病，其定义为肺动脉压 (PAP) 和肺血管阻力 (PVR) 升高，导致右心室 (RV) 重塑并经常死亡。PAH 中肺动脉硬度的早期增加驱动肺动脉内皮细胞 (PAEC) 的致病性改变，从而导致血管重塑。microRNA 的失调可导致 PAEC 功能障碍。然而，血管硬度在调节 PAH 致病性 microRNA 中的作用尚不完全清楚。在这里，我们证明了细胞外基质 (ECM) 硬化下调了 PAEC 中的 miR-7 水平。RNA 结合蛋白 Quaking (QKI) 与 miR-7 的生物发生有关。相应地，我们发现 ECM 刚度上调 QKI，QKI 敲低导致 miR-7 增加。在 QKI-miR-7 轴的下游，富含丝氨酸和精氨酸的剪接因子 1 (SRSF1) 被确定为 miR-7 的直接靶标。相应地，SRSF1 在暴露于僵硬 ECM 的 PAEC 中相互上调，并且与 miR-7 呈负相关。在暴露于 SU5416/缺氧的 PAH 患者和 PAH 大鼠的肺中观察到 miR-7 减少和 QKI 和 SRSF1 增加。最后，miR-7 上调抑制人 PAEC 迁移，而强制 SRSF1 表达逆转了这种表型，证明 miR-7 依赖于 SRSF1 来控制迁移。总之，这些结果将 QKI-miR-7-SRSF1 轴定义为将肺动脉血管硬度与致病性内皮功能联系起来的机械敏感机制。