Semaphorin-3A protects against neointimal hyperplasia after vascular injury
Semaphorin-3A protects against neointimal hyperplasia after vascular injury
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Semaphorin-3A 可防止血管损伤后的新内膜增生。
DOI：
10.1016/j.ebiom.2018.12.023
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发表时间：
2018-12
期刊：
影响因子：
11.1
通讯作者：
Hu Bo
中科院分区：
文献类型：
--
作者：
Wu Jie hong;Zhou Yi fan;Hong Can dong;Chen An qi;Luo Yan;Mao Ling;Xia Yuan peng;He Quan wei;Jin Hui juan;Huang Ming;Li Ya nan;Hu Bo
背景新生内膜增生是支架内再狭窄的重要病理学事件。血管平滑肌细胞（VSMC）从分化/收缩表型到去分化/合成表型的表型转换，伴随着VSMC的迁移和增殖，在新生内膜增生中起重要作用。然而，VSMCs的表型转换的分子机制尚未完全understood.MethodsThe小鼠颈动脉结扎模型建立，以评估Sema 3A的表达及其在体内新生内膜增生过程中的作用。利用生物信息学分析、染色质免疫沉淀（ChIP）分析和启动子-荧光素酶报告基因分析研究Sema 3A的表达调控机制。进行SiRNA转染和慢病毒感染以调节Sema 3A表达。EdU检测，伤口愈合划痕实验和Transwell迁移实验被用来评估VSMC增殖和migration.FindingsIn这项研究中，我们发现，脑信号蛋白-3A（Sema 3A）显着下调VSMC在血管损伤后的新生内膜增生小鼠和人动脉粥样硬化斑块。PDGF-BB通过p53下调VSMCs中Sema 3A的表达。此外，我们发现Sema 3A过表达抑制VSMC增殖和迁移，以及增加分化基因表达。从机制上讲，Sema 3A增加了NRP 1-丛蛋白-A1复合物，减少了NRP 1-PDGFRβ复合物，从而抑制了PDGFRβ的磷酸化。此外，我们发现，过度表达的Sema 3A抑制血管损伤后的新生内膜增生invivo.InterpretationThese结果表明，局部交付的Sema 3A可能作为一种新的治疗选择，以防止支架内再狭窄。
BackgroundNeointimal hyperplasia is a prominent pathological event during in-stent restenosis. Phenotype switching of vascular smooth muscle cells (VSMCs) from a differentiated/contractile to a dedifferentiated/synthetic phenotype, accompanied by migration and proliferation of VSMCs play an important role in neointimal hyperplasia. However, the molecular mechanisms underlying phenotype switching of VSMCs have yet to be fully understood.MethodsThe mouse carotid artery ligation model was established to evaluate Sema3A expression and its role during neointimal hyperplasia in vivo. Bioinformatics analysis, chromatin immunoprecipitation (ChIP) assays and promoter-luciferase reporter assays were used to examine regulatory mechanism of Sema3A expression. SiRNA transfection and lentivirus infection were performed to regulate Sema3A expression. EdU assays, Wound-healing scratch experiments and Transwell migration assays were used to assess VSMC proliferation and migration.FindingsIn this study, we found that semaphorin-3A (Sema3A) was significantly downregulated in VSMCs during neointimal hyperplasia after vascular injury in mice and in human atherosclerotic plaques. Meanwhile, Sema3A was transcriptionally downregulated by PDGF-BB via p53 in VSMCs. Furthermore, we found that overexpression of Sema3A inhibited VSMC proliferation and migration, as well as increasing differentiated gene expression. Mechanistically, Sema3A increased the NRP1-plexin-A1 complex and decreased the NRP1-PDGFRβ complex, thus inhibiting phosphorylation of PDGFRβ. Moreover, we found that overexpression of Sema3A suppressed neointimal hyperplasia after vascular injury in vivo.InterpretationThese results suggest that local delivery of Sema3A may act as a novel therapeutic option to prevent in-stent restenosis.
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影响因子：
44.1
作者：
Li-Hua Dong;J. Wen;Sui‐bing Miao;Z. Jia;Hai‐juan Hu;Rong‐hua Sun;Yiling Wu;Mei Han
通讯作者：
Li-Hua Dong;J. Wen;Sui‐bing Miao;Z. Jia;Hai‐juan Hu;Rong‐hua Sun;Yiling Wu;Mei Han
影响因子：
15.9
作者：
KHACHIGIAN, LM;RESNICK, N;COLLINS, T
通讯作者：
COLLINS, T
影响因子：
20.3
作者：
Shi, Guanfang;Field, David J.;Morrell, Craig N.
通讯作者：
Morrell, Craig N.
影响因子：
--
作者：
Movassagh H;Tatari N;Shan L;Koussih L;Alsubait D;Khattabi M;Redhu NS;Roth M;Tamm M;Chakir J;Gounni AS
通讯作者：
Gounni AS
DOI：
10.1016/j.omtn.2017.01.006
发表时间：
2017-03-17
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Koenig O;Nothdurft D;Perle N;Neumann B;Behring A;Degenkolbe I;Walker T;Schlensak C;Wendel HP;Nolte A
通讯作者：
Nolte A