Translational Stroke Research

, Volume 3, Issue 1, pp 138–145

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

  • Xiaojie Zhang
  • He Meng
  • Mila Blaivas
  • Elisabeth J. Rushing
  • Brian E. Moore
  • Jessica Schwartz
  • M. Beatriz S. Lopes
  • Bradford B. Worrall
  • Michael M. Wang
Original Article

DOI: 10.1007/s12975-011-0112-2

Cite this article as:
Zhang, X., Meng, H., Blaivas, M. et al. Transl. Stroke Res. (2012) 3: 138. doi:10.1007/s12975-011-0112-2

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.

Keywords

CADASILvon Willebrand Factor (vWF)Smooth muscleSmall-vessel diseaseVascular permeabilityImmunoglobulin

Copyright information

© Springer Science+Business Media, LLC (outside the U.S.) 2011

Authors and Affiliations

  • Xiaojie Zhang
    • 1
  • He Meng
    • 1
  • Mila Blaivas
    • 3
  • Elisabeth J. Rushing
    • 5
  • Brian E. Moore
    • 6
  • Jessica Schwartz
    • 2
  • M. Beatriz S. Lopes
    • 7
  • Bradford B. Worrall
    • 8
    • 9
  • Michael M. Wang
    • 1
    • 2
    • 4
  1. 1.Department of NeurologyUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Molecular and Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborUSA
  3. 3.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA
  4. 4.Department of NeurologyVA Ann Arbor Healthcare SystemAnn ArborUSA
  5. 5.Institute for NeuropathologyUniversitatsSpitalZurichSwitzerland
  6. 6.Department of Pathology and Center for Alzheimer’s Disease and Related DisordersSouthern Illinois University School of MedicineSpringfieldUSA
  7. 7.Department of PathologyUniversity of VirginiaCharlottesvilleUSA
  8. 8.Department of NeurologyUniversity of VirginiaCharlottesvilleUSA
  9. 9.Department of Public Health SciencesUniversity of VirginiaCharlottesvilleUSA