Department of Vascular Surgery, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, 215003, PR China.
Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, PR China.
Neuropharmacology. 2020 Mar 1;164:107858. doi: 10.1016/j.neuropharm.2019.107858. Epub 2019 Nov 27.
Dysfunction of vascular smooth muscle cells (VSMCs) may be linked to intracranial aneurysm (IA) formation. VSMCs possess a phenotypic plasticity, capable of changing from a mature, contractile to a less differentiated, synthetic phenotype. In this study, we identify a microRNA candidate miR-331-3p that participates in regulating differentiation properties of VSMCs. The expression of TNF-α and CD14 was quantified in IA wall tissues obtained from 96 IA patients and their associations with clinicopathological features of IA were assessed. Then the interactions between miR-331-3p, TNF-α and CD14 were evaluated by determination of luciferase activity. Differentiated properties of VSMCs were assessed from phenotypic markers of contractile VSMCs, a-SMA and E-cadherin, and of synthetic VSMCs, ICAM-1, MCP-1, IL-6, MMP-2 and MMP-9. Rat IA models by ligation of left carotid artery and left renal artery and histological analysis of induced IAs were performed. The TNF-α and CD14 was highly expressed in IA wall tissues and associated with the type and diameter of aneurysm. Depletion of TNF-α or CD14 retarded VSMC apoptosis and transformation to the synthetic type but facilitated cell proliferation. Elevations in miR-331-3p, a direct negative regulator of both TNF-α and CD14, also reduced VSMC apoptosis and prevented VSMCs from synthetic type and increase their proliferation. Furthermore, miR-331-3p was demonstrated to inhibit the formation of IA by down-regulating TNF-α and CD14 in vivo. In conclusion, miR-331-3p maintains the contractile type of VSMCs, thus possibly inhibiting the progression of IA. These findings provide potential new strategies for the clinical treatment of IA.
血管平滑肌细胞（VSMCs）功能障碍可能与颅内动脉瘤（IA）的形成有关。VSMCs具有表型可塑性，能够从成熟的收缩型转变为分化程度较低的合成型。在这项研究中，我们确定了一个参与调节 VSMC 分化特性的 microRNA 候选物 miR-331-3p。在 96 名 IA 患者的 IA 壁组织中定量检测 TNF-α和 CD14 的表达，并评估其与 IA 的临床病理特征的相关性。然后通过测定荧光素酶活性来评估 miR-331-3p、TNF-α和 CD14 之间的相互作用。通过检测收缩型 VSMC 的表型标志物 a-SMA 和 E-cadherin 以及合成型 VSMC 的标志物 ICAM-1、MCP-1、IL-6、MMP-2 和 MMP-9 来评估 VSMC 的分化特性。通过结扎左侧颈总动脉和左肾动脉建立大鼠 IA 模型，并对诱导的 IA 进行组织学分析。TNF-α和 CD14 在 IA 壁组织中高表达，并与动脉瘤的类型和直径相关。TNF-α或 CD14 的耗竭会延迟 VSMC 凋亡并促使其向合成型转化，但促进细胞增殖。直接负调控 TNF-α和 CD14 的 miR-331-3p 的升高也降低了 VSMC 凋亡并防止 VSMCs 向合成型转化，增加其增殖。此外，miR-331-3p 被证明通过下调 TNF-α和 CD14 抑制 IA 的形成。总之，miR-331-3p 维持 VSMC 的收缩型，从而可能抑制 IA 的进展。这些发现为 IA 的临床治疗提供了新的潜在策略。
