Vascular wall microenvironment:Endothelial cells original exosomes mediated melatonin-suppressed vascular calcification and vascular ageing in a m6A methylation dependent manner  

作　　者：Su-Kang Shan Xiao Lin Feng Wu Chang-Chun Li Bei Guo Fu-Xing-Zi Li Ming-Hui Zheng Yi Wang Qiu-Shuang Xu Li-Min Lei Ke-Xin Tang Yun-Yun Wu Jia-Yue Duan Ye-Chi Cao Yan-Lin Wu Chang-Ming Tan Zi-Han Liu Zhi-Ang Zhou Xiao-Bo Liao Feng Xu Ling-Qing Yuan 

机构地区：[1]National Clinical Research Center for Metabolic Diseases,Department of Metabolism and Endocrinology,The Second Xiangya Hospital of Central South University,Changsha,410011,Hunan,People’s Republic of China [2]Department of Radiology,The Second Xiangya Hospital of Central South University,Changsha,Hunan Province,410011,People’s Republic of China [3]Department of Pathology,The Second Xiangya Hospital of Central South University,Changsha,410011,People’s Republic of China [4]Department of Cardiothoracic Surgery,The Second Xiangya Hospital of Central South University,Changsha,410011,People’s Republic of China

出　　处：《Bioactive Materials》2024年第12期52-67,共16页生物活性材料（英文）

基　　金：supported by National Key Research&Development Program(No.2021YFC2501701 to LQY and FX);the National Natural Science Foundation of China(No.82370892 and 82070910 to LQY,No.82100494 to FX,No.82100944 and No.82470927 to XL,No.82200869 to FW);National Clinical Key Specialties Main Research Projects(2023026 to LQY);the Natural Science Foundation of Hunan Province(No.2022JJ40721 to FX);the Health Research Project in Hunan Province(No.20231696 to XL);the Scientific Research Launch Project for new employees of the Second Xiangya Hospital of Central South University(No.7673 to FX).

摘　　要：Vascular calcification and vascular ageing are“silent”diseases but are highly prevalent in patients with end stage renal failure and type 2 diabetes,as well as in the ageing population.Melatonin(MT)has been shown to induce cardiovascular protection effects.However,the role of MT on vascular calcification and ageing has not been well-identified.In this study,the aortic transcriptional landscape revealed clues for MT related cell-to-cell communication between endothelial cells(ECs)and vascular smooth muscle cells(VSMCs)in vascular calcification and vascular ageing.Furthermore,we elucidated that it was exosomes that participate in the information transportation from ECs to VSMCs.The exosomes secreted from melatonin-treated ECs(MT-ECs-Exos)inhibited calcification and senescence of VSMCs.Mechanistically,miR-302d-5p was highly enriched in MT-ECs-Exos,while depletion of miR-302d-5p blocked the ability of MT-ECs-Exos to suppress VSMC calcification and senescence.Notably,Wnt3 was a bona fide target of miR-302d-5p and modulated VSMC calcification and senescence.Furthermore,we found that maturation of endothelial derived exosomal miR-302d-5p was promoted by WTAP in an N^(6)-methyladenosine(m^(6)A)-dependent manner.Interestingly,MT alleviated vascular calcification and ageing in 5/6-nephrectomy(5/6 NTP)mice,a chronic kidney disease(CKD)induced vascular calcification and vascular ageing mouse model.MT-ECs-Exos was absorbed by VSMCs in vivo and effectively prevented vascular calcification and ageing in 5/6 NTP mice.ECs-derived miR-302d-5p mediated MT induced anti-calcification and anti-ageing effects in 5/6 NTP mice.Our study suggests that MT-ECs-Exos alleviate vascular calcification and ageing through the miR-302d-5p/Wnt3 signaling pathway,dependent on m^(6)A methylation.

关 键 词：MELATONIN Vascular calcification Vascular ageing EXOSOMES N6-methyladenosine 

分 类 号：R54[医药卫生—心血管疾病]