von Willebrand Factor Permeates Small Vessels in CADASIL and Inhibits Smooth Muscle Gene Expression
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ORIGINAL ARTICLE
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
Received: 31 July 2011 / Revised: 9 September 2011 / Accepted: 3 October 2011 / Published online: 20 October 2011 # Springer Science+Business Media, LLC (outside the USA) 2011
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 X. Zhang : H. Meng : M. M. Wang Department of Neurology, University of Michigan Medical School, 1301 E. Catherine St., 7629 Medical Science II, Ann Arbor, MI 48109, USA J. Schwartz : M. M. Wang Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA M. Blaivas Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA M. M. Wang (*) Department of Neurology, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105, USA e-mail: [email protected]
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.
E. J. Rushing Institute for Neuropathology, UniversitatsSpital, CH-8091 Zurich, Switzerland B. E. Moore Department of Pathology and Center for Alzheimer’s Disease and Related Disorders, Southern Illinois University School of Medicine, Springfield, IL 62794, USA M. B. S. Lopes Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA B. B. Worrall Departm
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