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von Willebrand Factor Permeates Small Vessels in CADASIL and Inhibits Smooth Muscle Gene Expression

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder hallmarked by ischemic stroke and vascular dementia. Characteristic pathological changes in the vasculature include thickening of small arteries and accumulation of heterogeneous material within the vessel wall. We tested whether endothelial von Willebrand factor (vWF) accumulates in CADASIL vessels and whether exposure of smooth muscle cells to vWF alters the expression of smooth muscle gene expression. Brain sections obtained at autopsy from six North American CADASIL patients were examined using immunohistochemistry for vWF and IgG. Rat aortic smooth muscle cells (A7R5 cells) were tested for binding to infrared tag-labeled vWF. Finally, A7R5 cells were exposed to vWF, and expression of mature smooth muscle marker genes was analyzed by quantitative reverse transcriptase PCR. vWF is expressed in the penetrating arterial walls in all CADASIL samples. IgG, a marker of serum extravasation, was present only in a minority of arterial walls. vWF binds to smooth muscle cells in vitro, and low concentrations of vWF rapidly activate c-Fos, Egr-1, TSP1, and c-Myc while specifically inhibiting RNA encoding smooth muscle actin, calponin, and SM22. These data demonstrate that vWF, likely produced by the endothelium, permeates the vessel wall of CADASIL brains. Exposure of smooth muscle cells to vWF results in reduction of specific RNAs required for normal vascular homeostasis. This is the first report of accumulation of a protein within CADASIL vessels that inhibits vascular gene expression and implicates a role for vWF beyond hemostasis.

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Acknowledgments

We thank the patients and families who donated tissues for this study. We also acknowledge the generous resources provided by the University of Michigan Alzheimer's Disease Research Center (funded by NIH P50 AG008761-20-SI), who provided control tissues. Other human tissues were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, contract HHSN275200900011C, ref. no. NO1-HD-9-0011. Shannon Dunn contributed to c-Fos luciferase studies.

Sources of Funding

This study was supported by grants NS054724 and NS062816 from NIH-NINDS and VA Merit award 5I01BX000375.

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Authors and Affiliations

  1. Department of Neurology, University of Michigan Medical School, 1301 E. Catherine St., 7629 Medical Science II, Ann Arbor, MI, 48109, USA

    Xiaojie Zhang, He Meng & Michael M. Wang

  2. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Jessica Schwartz & Michael M. Wang

  3. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Mila Blaivas

  4. Department of Neurology, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI, 48105, USA

    Michael M. Wang

  5. Institute for Neuropathology, UniversitatsSpital, CH-8091, Zurich, Switzerland

    Elisabeth J. Rushing

  6. Department of Pathology and Center for Alzheimer’s Disease and Related Disorders, Southern Illinois University School of Medicine, Springfield, IL, 62794, USA

    Brian E. Moore

  7. Department of Pathology, University of Virginia, Charlottesville, VA, 22908, USA

    M. Beatriz S. Lopes

  8. Department of Neurology, University of Virginia, Charlottesville, VA, 22908, USA

    Bradford B. Worrall

  9. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908, USA

    Bradford B. Worrall

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  1. Xiaojie Zhang
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  2. He Meng
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  7. M. Beatriz S. Lopes
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  9. Michael M. Wang
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Correspondence to Michael M. Wang.

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Zhang, X., Meng, H., Blaivas, M. et al. von Willebrand Factor Permeates Small Vessels in CADASIL and Inhibits Smooth Muscle Gene Expression. Transl. Stroke Res. 3, 138–145 (2012). https://doi.org/10.1007/s12975-011-0112-2

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  • DOI: https://doi.org/10.1007/s12975-011-0112-2

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