Yang Shuang, Li Hou-Wei, Tian Jia-Ying, Wang Zheng-Kai, Chen Yi, Zhan Ting-Ting, Ma Chun-Yue, Feng Min, Cao Shi-Feng, Zhao Yu, Li Xue, Ren Jing, Liu Qian, Jin Lu-Ying, Wang Zhi-Qi, Jiang Wen-Yu, Zhao Yi-Xiu, Zhang Yan, Liu Xue
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, National-Local Joint Engineering Laboratory for Drug Research and Development of Cardio-Cerebrovascular Diseases in Frigid Zone, the National Development and Reform Commission, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150086, China.
National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin, 150086, China.
Acta Pharmacol Sin. 2024 Jan;45(1):98-111. doi: 10.1038/s41401-023-01155-x. Epub 2023 Sep 19.
Restenosis after angioplasty is caused usually by neointima formation characterized by aberrant vascular smooth muscle cell (VSMC) dedifferentiation. Myeloid-derived growth factor (MYDGF), secreted from bone marrow-derived monocytes and macrophages, has been found to have cardioprotective effects. In this study we investigated the effect of MYDGF to postinjury neointimal formation and the underlying mechanisms. Rat carotid arteries balloon-injured model was established. We found that plasma MYDGF content and the level of MYDGF in injured arteries were significantly decreased after balloon injury. Local application of exogenous MYDGF (50 μg/mL) around the injured vessel during balloon injury markedly ameliorated the development of neointimal formation evidenced by relieving the narrow endovascular diameter, improving hemodynamics, and reducing collagen deposition. In addition, local application of MYDGF inhibited VSMC dedifferentiation, which was proved by reversing the elevated levels of osteopontin (OPN) protein and decreased levels of α-smooth muscle actin (α-SMA) in the left carotid arteries. We showed that PDGF-BB (30 ng/mL) stimulated VSMC proliferation, migration and dedifferentiation in vitro; pretreatment with MYDGF (50-200 ng/mL) concentration-dependently eliminated PDGF-BB-induced cell proliferation, migration and dedifferentiation. Molecular docking revealed that MYDGF had the potential to bind with sphingosine-1-phosphate receptor 2 (S1PR2), which was confirmed by SPR assay and Co-IP analysis. Pretreatment with CCG-1423 (Rho signaling inhibitor), JTE-013 (S1PR2 antagonist) or Ripasudil (ROCK inhibitor) circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching through inhibiting S1PR2 or its downstream RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling. In summary, this study proves that MYDGF relieves neointimal formation of carotid arteries in response to balloon injury in rats, and suppresses VSMC dedifferentiation induced by PDGF-BB via S1PR2-RhoA-G/F-actin-MRTF-A signaling pathway. In addition, our results provide evidence for cross talk between bone marrow and vasculature.
血管成形术后再狭窄通常由新生内膜形成引起，其特征为血管平滑肌细胞（VSMC）异常去分化。骨髓来源的单核细胞和巨噬细胞分泌的髓样衍生生长因子（MYDGF）已被发现具有心脏保护作用。在本研究中，我们调查了MYDGF对损伤后新生内膜形成的影响及其潜在机制。建立大鼠颈动脉球囊损伤模型。我们发现球囊损伤后血浆MYDGF含量和损伤动脉中MYDGF水平显著降低。在球囊损伤期间在损伤血管周围局部应用外源性MYDGF（50μg/mL）可显著改善新生内膜形成的发展，表现为缓解血管内径狭窄、改善血流动力学和减少胶原沉积。此外，局部应用MYDGF抑制了VSMC去分化，这通过逆转左颈动脉中骨桥蛋白（OPN）蛋白水平升高和α-平滑肌肌动蛋白（α-SMA）水平降低得到证实。我们发现血小板衍生生长因子-BB（PDGF-BB，30ng/mL）在体外刺激VSMC增殖、迁移和去分化；用MYDGF（50-200ng/mL）预处理以浓度依赖的方式消除了PDGF-BB诱导的细胞增殖、迁移和去分化。分子对接显示MYDGF有可能与1-磷酸鞘氨醇受体2（S1PR2）结合，表面等离子体共振（SPR）分析和免疫共沉淀（Co-IP）分析证实了这一点。用CCG-1423（Rho信号抑制剂）、JTE-013（S1PR2拮抗剂）或利马前列素（ROCK抑制剂）预处理通过抑制S1PR2或其下游RhoA-肌动蛋白单体（G-肌动蛋白）/肌动蛋白丝（F-肌动蛋白）-心肌相关转录因子A（MRTF-A）信号通路，规避了MYDGF对VSMC表型转换的抑制作用。总之，本研究证明MYDGF可缓解大鼠球囊损伤后颈动脉的新生内膜形成，并通过S1PR2-RhoA-G/F-肌动蛋白-MRTF-A信号通路抑制PDGF-BB诱导的VSMC去分化。此外，我们的结果为骨髓与血管系统之间的串扰提供了证据。
