RATIONALE Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. OBJECTIVES To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. METHODS AND RESULTS Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214-/- prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfb1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214-/- mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into perivascular adipose tissue was abolished in miR-214-/- mice. Adoptive transfer of miR-214-/- T cells into RAG1-/- mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214-/-. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214-/- prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-α, IL-9, and IFN-γ) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. CONCLUSIONS T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release.

中文翻译：

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T细胞衍生的miRNA-214在高血压中介导血管周围纤维化。

理由尽管对高血压与血管周纤维化有关的血管僵硬的预后重要性越来越了解，但对该过程的分子和细胞调节知之甚少。目的研究microRNA-214（miR-214）在诱导血管周围纤维化和驱动血管硬化的内皮功能障碍中的功能。方法和结果在响应Ang II（血管紧张素II）介导的高血压的血管周组织中筛选的381个miR中，miR-214的诱导率最高（8倍，P = 0.0001）。MiR-214诱导在血管周和循环T细胞中明显，但在血管周脂肪组织脂肪细胞中不明显。全局删除miR-214-/-预防Ang II诱导的腹主动脉纤维化，Col1a1，Col3a1，Col5a1和Tgfb1表达，羟脯氨酸积累，和血管硬化，血压无差异。机理研究表明，miR-214-/-小鼠可免受内皮功能障碍，氧化应激和Nox2含量升高的影响，所有这些均是由WT II的Ang II诱导的。在miR-214-/-小鼠中取消了Ang II诱导的T细胞募集到血管周脂肪组织中。与WT T细胞的作用相比，miR-214-/-T细胞过继转移到RAG1-/-小鼠中导致血管周纤维化的减少。Ang II诱导的高血压引起WT中1380 T细胞基因表达的显着变化，而miR-214-/-中只有51表达。T细胞的活化，增殖和趋化途径受到不同的影响。MiR-214-/-预防了Ang II诱导的纤维化T细胞细胞因子（IL-17，TNF-α，IL-9和IFN-γ）和趋化因子受体（CCR1，CCR2，CCR4，CCR5，CCR6和CXCR3）。这表现为体外和体内T细胞趋化性降低，导致纤维化血管周围炎症的减弱。从翻译上，我们表明，miR-214在高血压患者的血浆中增加，并且与脉搏波速度直接相关，以衡量血管的僵硬程度。结论T细胞源性miR-214可控制由T细胞募集和局部纤维化细胞因子释放介导的高血压的病理性血管周纤维化。