Delta-like factor 1 negatively regulates angiogenesis as a target gene of miR-126-5p after indirect revascularization surgery in patients with moyamoya disease
Delta-like factor 1 negatively regulates angiogenesis as a target gene of miR-126-5p after indirect revascularization surgery in patients with moyamoya disease
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烟雾病患者间接血运重建手术后，Delta 样因子 1 作为 miR-126-5p 的靶基因负向调节血管生成
DOI：
10.3126/njn.v19i2.43886
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Chuan Chen
中科院分区：
文献类型：
--
作者：
Yang Yang;Cong Ling;Shuangqi Gao;Robin Bhattarai;Robin Bhattarai;Hailong Wang;Chuan Chen
间接血运重建术后促进内皮细胞（EC）增殖和血管生成对降低烟雾病患者卒中发生率至关重要。然而，delta-like factor 1 （DLK1）在慢性缺血脑中调控EC增殖中的作用及其具体机制尚不清楚。因此，我们比较了DLK1在烟雾病患者和动脉瘤患者的硬脑膜（DM）组织中的表达水平，并通过双荧光素酶报告基因和RNA结合蛋白免疫沉淀实验来确定DLK1是否是miR-126-5p的靶基因。我们在体外探讨DLK1对EC增殖的影响以及DLK1与miR-126-5p的相互作用。然后，我们建立了双血管闭塞合并脑肌合症（2VO+EMS）的动物模型。用DLK1慢病毒RNA （Lv-DLK1）和短发夹RNA （sh-DLK1）转染动物颞肌（TMs），比较各组慢性缺血脑DLK1表达、血管生成（CD31计数）、空泡数量和ECs紧密连接受损情况以及认知改善情况。DLK1在烟雾病患者DM组织中的表达低于动脉瘤患者，DLK1被确定为miR-126-5p的靶基因。在体外，DLK1抑制EC的增殖、迁移和血管生成，其作用与miR-126-5p相反。在2VO+EMS大鼠中，与对照组相比，TM转染Lv-DLK1可显著提高DLK1的表达，使TM覆盖的缺血脑内血管生成变差，认知改善的广泛性降低，而sh-DLK1转染TM则具有相反的效果。综上所述，miR-126-5p的靶基因DLK1负调控慢性缺血脑血管生成，有望成为改善间接血运重建术疗效和烟雾病患者预后的新靶点。
Promoting endothelial cell (EC) proliferation and angiogenesis after indirect revascularization surgery is crucial for decreasing the stroke rate in moyamoya patients. However, the role of delta-like factor 1 (DLK1) in regulating EC proliferation in chronically ischaemic brains and the specific mechanisms remain unclear. Therefore, we compared the expression levels of DLK1 in the dura mater (DM) tissues of patients with moyamoya disease and patients with aneurysms, and dual luciferase reporter and RNA binding protein immunoprecipitation assays were conducted to determine whether DLK1 is a target gene of miR-126-5p. The effect of DLK1 on EC proliferation and the interaction between DLK1 and miR-126-5p were explored in vitro. Then, we established an animal model of two-vessel occlusion together with encephalo-myo-synangiosis (2VO+EMS). The temporalis muscles (TMs) of the animals were transfected with DLK1 lentiviral RNA (Lv-DLK1) and short hairpin RNA (sh-DLK1) to compare the DLK1 expression, angiogenesis (CD31 count), and numbers of vacuoles and impaired tight junctions in the ECs of TM-covered chronically ischaemic brains as well as the cognitive improvement in each group. DLK1 expression was lower in the DM tissues of moyamoya patients than in those of the aneurysm patients, and DLK1 was identified as a target gene of miR-126-5p. In vitro, DLK1 inhibited EC proliferation, migration and angiogenesis and exerted effects opposite those of miR-126-5p. In 2VO+EMS rats, compared to the control transfection, the TM transfection of Lv-DLK1 induced significantly higher DLK1 expression and worse angiogenesis in the TM-covered ischaemic brain as well as less extensive cognitive improvement, while the transfection of sh-DLK1 into the TM had the opposite effects. In summary, DLK1, a target gene of miR-126-5p, negatively regulates angiogenesis in chronically ischaemic brains and is expected to be a new target to improve the efficacy of indirect revascularization surgery and the prognosis of moyamoya patients.
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DOI：
10.1096/fj.202002674rr
发表时间：
2021-07
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Nguyen H;Koh JY;Li H;Islas-Robles A;Meda Venkata SP;Wang JM;Monks TJ
通讯作者：
Monks TJ
影响因子：
82.9
作者：
通讯作者：
--
增加颞肌中 microRNA-126-5p 的表达可促进两血管闭塞加脑肌联结大鼠慢性缺血脑中的血管生成
影响因子：
5.2
作者：
Chen, Chuan;Ling, Cong;Guo, Ying
通讯作者：
Guo, Ying
影响因子：
12.4
作者：
Tasfaout, Hichem;Lionello, Valentina M.;Cowling, Belinda S.
通讯作者：
Cowling, Belinda S.
DOI：
10.1016/j.neo.2020.10.005
发表时间：
2020-12
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Grassi ES;Jeannot P;Pantazopoulou V;Berg TJ;Pietras A
通讯作者：
Pietras A