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MYPT1SMKO Mice Function as a Novel Spontaneous Age- and Hypertension-Dependent Animal Model of CSVD

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Abstract

Cerebral small vessel disease (CSVD) is the most common progressive vascular disease that causes vascular dementia. Aging and hypertension are major contributors to CSVD, but the pathophysiological mechanism remains unclear, mainly due to the lack of an ideal animal model. Our previous study revealed that vascular smooth muscle cell (VSMC)-specific myosin phosphatase target subunit 1 (MYPT1) knockout (MYPT1SMKO) leads to constant hypertension, prompting us to explore whether hypertensive MYPT1SMKO mice can be considered a novel CSVD animal model. Here, we found that MYPT1SMKO mice displayed age-dependent CSVD-like neurobehaviors, including decreased motion speed, anxiety, and cognitive decline. MYPT1SMKO mice exhibited remarkable white matter injury compared with control mice, as shown by the more prominent loss of myelin at 12 months of age. Additionally, MYPT1SMKO mice were found to exhibit CSVD-like small vessel impairment, including intravascular hyalinization, perivascular space enlargement, and microbleed and blood-brain barrier (BBB) disruption. Last, our results revealed that the brain of MYPT1SMKO mice was characterized by an exacerbated inflammatory microenvironment, which is similar to patients with CSVD. In light of the above structural and functional phenotypes that closely mimic the conditions of human CSVD, we suggest that MYPT1SMKO mice are a novel age- and hypertension-dependent animal model of CSVD.

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Data Availability

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

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Acknowledgements

We thank Feng Han and Meiling Sun from Nan**g Medical University in China for their help in the two-photon imaging analysis.

Funding

This study was funded by the National Natural Science Foundation of China (82130036, 81920108017), the National Science and Technology Innovation 2030—Major program of “Brain Science and Brain-Like Research” 2022ZD0211800, the Key Research and Development Program of Jiangsu Province of China (BE2020620). Jiangsu Province Key Medical Discipline (ZDXKA2016020).

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  1. Jian Chen and Cheng-Gang Li contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nan**g University, Nan**g, 210008, China

    Jian Chen, Cheng-Gang Li, Li-Xuan Yang, Yi Qian, Li-Wen Zhu, Pin-Yi Liu, **ang Cao, Ye Wang, Min-Sheng Zhu & Yun Xu

  2. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nan**g University, Nan**g, 210008, China

    Min-Sheng Zhu & Yun Xu

  3. Jiangsu Provincial Key Discipline of Neurology, Nan**g, 210008, China

    Yun Xu

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Contributions

YX designed research; JC, C-GL, L-XY, YQ, L-WZ, and P-YL performed research; JC, L-XY, and C-GL analyzed data; M-SZ developed the mice; YW assisted with animal breed; JC, YX wrote the paper. YX and M-SZ revised the paper. All authors reviewed and approved the manuscript.

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Correspondence to Min-Sheng Zhu or Yun Xu.

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All the animal experiments were conducted according to institutional guidelines and were approved by the Animal Use and Care Committees at Nan**g University.

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Chen, J., Li, CG., Yang, LX. et al. MYPT1SMKO Mice Function as a Novel Spontaneous Age- and Hypertension-Dependent Animal Model of CSVD. Transl. Stroke Res. 15, 606–619 (2024). https://doi.org/10.1007/s12975-023-01142-8

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