Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark.
Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
J Cardiovasc Pharmacol. 2019 Nov;74(5):409-419. doi: 10.1097/FJC.0000000000000735.
Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with a high short-term mortality rate which leads to cognitive impairments that reduce the quality of life of the majority of patients. The miRNA-143/145 cluster is highly expressed in vascular smooth muscle cells (VSMC) and has been shown to be necessary for differentiation and function, as well as an important determinant for phenotypic modulation/switching of VSMCs in response to vascular injury. We aimed to determine whether miRNA-143 and miRNA-145 are important regulators of phenotypical changes of VSMCs in relation to SAH, as well as establishing their physiological role in the cerebral vasculature. We applied quantitative PCR to study ischemia-induced alterations in the expression of miRNA-143 and miRNA-145, for rat cerebral vasculature, in an ex vivo organ culture model and an in vivo SAH model. To determine the physiological importance, we did myograph studies on basilar and femoral arteries from miRNA-143/145 knockout mice. miRNA-143 and miRNA-145 are not upregulated in the vasculature following our SAH model, despite the upregulation of miR-145 in the organ culture model. Regarding physiological function, miRNA-143 and miRNA-145 are very important for general contractility in cerebral vessels in response to depolarization, angiotensin II, and endothelin-1. Applying an anti-miRNA targeting approach in SAH does not seem to be a feasible approach because miRNA-143 and miRNA-145 are not upregulated following SAH. The knockout mouse data suggest that targeting miRNA-143 and miRNA-145 would lead to a general reduced contractility of the cerebral vasculature and unwanted dedifferentiation of VSMCs.
蛛网膜下腔出血（SAH）是一种出血性中风，其短期死亡率较高，导致认知障碍，降低了大多数患者的生活质量。miRNA-143/145 簇在血管平滑肌细胞（VSMC）中高度表达，已被证明对分化和功能是必要的，并且是 VSMC 对血管损伤反应的表型调节/转换的重要决定因素。我们旨在确定 miRNA-143 和 miRNA-145 是否是与 SAH 相关的 VSMC 表型变化的重要调节剂，并确定它们在脑血管中的生理作用。我们应用定量 PCR 研究了在体外器官培养模型和体内 SAH 模型中，miRNA-143 和 miRNA-145 在缺血诱导的大鼠脑血管表达变化。为了确定生理重要性，我们对 miRNA-143/145 敲除小鼠的基底动脉和股动脉进行了肌描记研究。尽管在器官培养模型中 miR-145 上调，但在我们的 SAH 模型中，血管中 miRNA-143 和 miRNA-145 没有上调。关于生理功能，miRNA-143 和 miRNA-145 对于大脑血管对去极化、血管紧张素 II 和内皮素-1的一般收缩性非常重要。在 SAH 中应用抗 miRNA 靶向方法似乎不可行，因为 SAH 后 miRNA-143 和 miRNA-145 没有上调。敲除小鼠数据表明，靶向 miRNA-143 和 miRNA-145 会导致大脑血管的一般收缩性降低和 VSMC 的不必要去分化。
