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Redistribution of Mature Smooth Muscle Markers in Brain Arteries in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

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Abstract

Vascular smooth muscle cells (SMCs) undergo a series of dramatic changes in CADASIL, the most common inherited cause of vascular dementia and stroke. NOTCH3 protein accumulates and aggregates early in CADASIL, followed by loss of mature SMCs from the media of brain arteries and marked intimal proliferation. Similar intimal thickening is seen in peripheral arterial disease, which features pathological intimal cells including proliferative, dedifferentiated, smooth muscle-like cells deficient in SMC markers. Limited studies have been performed to investigate the differentiation state and location of SMCs in brain vascular disorders. Thus, we investigated the distribution of cells expressing SMC markers in a group of genetically characterized, North American CADASIL brains. We quantified brain RNA abundance of these markers in nine genetically verified cases of CADASIL and found that mRNA expression for several mature SMC markers was increased in CADASIL brain compared to age-matched control. Immunohistochemical studies and in situ hybridization localization of mRNA demonstrated loss of SMCs from the arterial media, and SMC marker-expressing cells were instead redistributed into the intima of diseased arteries and around balloon cells of the degenerating media. We conclude that, despite loss of medial smooth muscle cells in diseased arteries, smooth muscle markers are not lost from CADASIL brain, but rather, the localization of cells expressing mature SMC markers changes dramatically.

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Fig. 1: Transcripts of smooth muscle markers are increased in CADASIL; transcripts of endothelial markers are either increased or not significantly altered.
Fig. 2: Expression of smooth muscle proteins in the intima of leptomeningeal vessels in CADASIL brain.
Fig. 3: Expression of smooth muscle proteins in the intima of small penetrating vessels in CADASIL brain.
Fig. 4: Mature smooth muscle genes are actively transcribed in intimal and balloon cells of CADASIL vessels.
Fig. 5: Balloon cell frequency in CADASIL and expression of smooth muscle marker proteins in balloon cells of CADASIL leptomeningeal arteries.
Fig. 6: Vascular smooth muscle mRNA expression in balloon cells of CADASIL. In situ hybridization for vascular smooth muscle marker mRNA was performed on CADASIL cortical sections.

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Acknowledgements

We appreciate the support of CADASIL Together We Have Hope and members of the international CADASIL community who made donations used in this study.

Funding

This study was funded by the National Institutes of Health (NS099783 and HL108842) and the U.S. Department of Veterans Affairs (BX000375 and BX003824).

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  1. John R. Gatti and Xiaojie Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, University of Michigan, Ann Arbor, MI, 48109-5622, USA

    John R. Gatti, Xiaojie Zhang, Ejona Korcari, Soo Jung Lee, Nya Greenstone, Snehaa Maripudi & Michael M. Wang

  2. Department Molecular & Integrative Physiology, University of Michigan, 7625 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA

    Jon G. Dean & Michael M. Wang

  3. Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA

    Michael M. Wang

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  1. John R. Gatti
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Correspondence to Michael M. Wang.

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Gatti, J.R., Zhang, X., Korcari, E. et al. Redistribution of Mature Smooth Muscle Markers in Brain Arteries in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Transl. Stroke Res. 10, 160–169 (2019). https://doi.org/10.1007/s12975-018-0643-x

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