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Shear Stress-Induced miR-143-3p in Collateral Arteries Contributes to Outward Vessel Growth by Targeting Collagen V-α2.
Arteriosclerosis, Thrombosis, and Vascular Biology ( IF 8.7 ) Pub Date : 2020-03-19 , DOI: 10.1161/atvbaha.120.313316
Kerstin Troidl 1, 2 , Thomas Hammerschick 3 , Julian Albarran-Juarez 1, 4 , Georg Jung 2 , Wilma Schierling 5 , Sarah Tonack 1 , Marcus Krüger 6 , Benjamin Matuschke 3 , Christian Troidl 7, 8 , Wolfgang Schaper 1 , Thomas Schmitz-Rixen 2 , Klaus T Preissner 3 , Silvia Fischer 3
Affiliation  

OBJECTIVE Arteriogenesis, describing the process of collateral artery growth, is activated by fluid shear stress (FSS). Since this vascular mechanotransduction may involve microRNAs (miRNAs), we investigated the FSS-induced expression of vascular cell miRNAs and their functional impact on collateral artery growth during arteriogenesis. Approach and Results: To this end, rats underwent femoral artery ligation and arteriovenous anastomosis to increase collateral blood flow to maximize FSS and trigger collateral vessel remodeling. Five days after surgery, a miRNA expression profile was obtained from collateral tissue, and upregulation of 4 miRNAs (miR-24-3p, miR-143-3p, miR-146a-5p, and miR-195-5p) was verified by quantitative polymerase chain reaction. Knockdown of miRNAs at the same time of the surgery in an in vivo mouse ligation and recovery model demonstrated that inhibition of miR-143-3p only severely impaired blood flow recovery due to decreased arteriogenesis. In situ hybridization revealed distinct localization of miR-143-3p in the vessel wall of growing collateral arteries predominantly in smooth muscle cells. To investigate the mechanotransduction of FSS leading to the increased miR-143-3p expression, cultured endothelial cells were exposed to FSS. This provoked the expression and release of TGF-β (transforming growth factor-β), which increased the expression of miR-143-3p in smooth muscle cells in the presence of SRF (serum response factor) and myocardin. COL5A2 (collagen type V-α2)-a target gene of miR-143-3p predicted by in silico analysis-was found to be downregulated in growing collaterals. CONCLUSIONS These results indicate that the increased miR-143-3p expression in response to FSS might contribute to the reorganization of the extracellular matrix, which is important for vascular remodeling processes, by inhibiting collagen V-α2 biosynthesis.

中文翻译:

剪切应力在侧支动脉中诱导的miR-143-3p通过靶向胶原V-α2促进了血管的向外生长。

目的动脉生成,描述了侧支动脉的生长过程,由流体剪切应力(FSS)激活。由于这种血管机械转导可能涉及microRNA(miRNA),因此我们研究了FSS诱导的血管细胞miRNA表达及其在动脉生成过程中对侧支动脉生长的功能影响。方法和结果:为此,对大鼠进行股动脉结扎和动静脉吻合术,以增加侧支血流,以最大化FSS并触发侧支血管重塑。手术五天后,从侧支组织获得了miRNA表达谱,并通过定量验证了4种miRNA(miR-24-3p,miR-143-3p,miR-146a-5p和miR-195-5p)的上调聚合酶链反应。在体内小鼠结扎和恢复模型中,在手术同时敲除miRNA的结果表明,抑制miR-143-3p仅会严重降低动脉生成,从而严重损害血流恢复。原位杂交揭示了miR-143-3p在侧支动脉生长的血管壁中的独特定位,主要是在平滑肌细胞中。为了研究导致增加的miR-143-3p表达的FSS的机械转导,将培养的内皮细胞暴露于FSS。这激起了TGF-β(转化生长因子-β)的表达和释放,这在存在SRF(血清反应因子)和心肌素的情况下增加了平滑肌细胞中miR-143-3p的表达。通过计算机分析预测,miR-143-3p的靶基因COL5A2(胶原蛋白V-α2型)在生长的侧支中被下调。结论这些结果表明,响应FSS的miR-143-3p表达增加可能通过抑制胶原V-α2的生物合成来促进细胞外基质的重组,这对于血管重塑过程很重要。
更新日期:2020-03-19
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