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Endothelial Cell–Derived Let-7c-Induced TLR7 Activation on Smooth Muscle Cell Mediate Vascular Wall Remodeling in Moyamoya Disease

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Abstract

Moyamoya disease (MMD) is characterized by frequent migration and phenotypic transformation of vascular smooth muscle cells (VSMCs) in the intima layer of blood vessels. However, the underlying mechanism is unclear. Toll-like receptor (TLR) 7 is abundantly expressed in smooth muscle cells (SMCs) in multiple vascular diseases, which might be linked to the disease-associated vascular remodeling. In the present study, the expression of TLR7 in MMD vessels was examined using the superficial temporal artery (STA) and middle cerebral artery (MCA) from MMD patients. Furthermore, the effect of TLR7 activation on the VSMC phenotype switch in vitro and vascular remodeling in vivo was assessed using a 9.4Tesla MRI. Our results demonstrated that the TLR7 and microRNA Let-7c expression are upregulated in VSMCs and the plasma of MMD patients, respectively. Additionally, TLR7 stimulation by Let-7c or Imiquimod induces a synthetic phenotype switch in VSMCs. Mechanistic studies revealed that Akt/mTOR signaling is responsible for this TLR-induced VSMC phenotypic switch. The Let-7c or Imiquimod treatment also resulted in reduced blood flow of internal carotid arteries (ICAs) in an in vivo model, while TLR7 inhibition attenuated the ICA stenosis. Besides, Let-7c was also found to be elevated in the hypoxic endothelial cells. Taken together, our study demonstrates that Let-7c released by endothelial cells under hypoxic conditions may activate TLR7 on VSMCs, ultimately leading to the phenotype switch and vascular wall remodeling. These findings thus elucidate the putative mechanisms underlying progressive stenosis of blood vessels in MMD and provide prospective therapeutic targets for further exploration.

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Data Availability

The data used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the Laboratory Core Facility of Tongji Hospital of Tongji Medical College, Wuhan, 430030, People’s Republic of China, for technical assistance. We would also like to especially acknowledge Dr. Qing Li for kindly sharing the cells used in the study with us and providing technical assistance. This study was supported by the Natural Science Foundation of Hubei Province (WJ2019Z008) and the Natural Science Foundation of Tongji Hospital (2020JZKT651), People’s Republic of China.

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Author notes

  1. Xiaopeng Ma and Yimin Huang contributed equally to this work.

  2. Sheng Wang and Huaqiu Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, 430030, Hubei Province, China

    Xiaopeng Ma, Yimin Huang, Xuejun He, Xincheng Zhang, Yanchao Liu, Yiping Yang, Pengjie Yue, Yuan Liu, Chao Gan, Kai Shu, Ting Lei, Sheng Wang & Huaqiu Zhang

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Supplementary Figure 1

qPCR (a) and Westernblot (b) assay was used to determine the transfection efficiency of TLR7 siRNA on VSMCs. (PNG 113 kb)

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Ma, X., Huang, Y., He, X. et al. Endothelial Cell–Derived Let-7c-Induced TLR7 Activation on Smooth Muscle Cell Mediate Vascular Wall Remodeling in Moyamoya Disease. Transl. Stroke Res. 14, 608–623 (2023). https://doi.org/10.1007/s12975-022-01088-3

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