Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications

Brulin, Peggy; Godfraind, Catherine; Leteurtre, Emmanuelle; Ruchoux, Marie‐Magdeleine

doi:10.1007/s00401-002-0530-z

Cited by 69 publications

(35 citation statements)

References 22 publications

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“…Ultrastructural studies have demonstrated widening of cell-cell distances between smooth muscle cells in CADASIL [34, 35]. As such, potential explanations for the penetration of vWF through the vascular media may include compromise of the basement membrane and intercellular matrix between smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Meng

Blaivas

et al. 2011

Transl. Stroke Res.

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Background and Purpose CADASIL (cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy) 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. Methods 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. Results 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, TSP1, and c-myc while specifically inhibiting RNA encoding smooth muscle actin, calponin, and SM22. Conclusions 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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Section: Discussionmentioning

confidence: 99%

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

Zhang

Meng

Blaivas

et al. 2011

Transl. Stroke Res.

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“…The postnatal expression of the gene is mostly restricted to vascular smooth muscle cells (VSMCs) of middle and small arteries and pericytes [1], [3]. The mutations are associated with accumulation of the NOTCH3 extracellular domain in the wall of small cerebral arteries, resulting in VSMC degeneration [4], [5], [6].…”

Section: Introductionmentioning

confidence: 99%

“…Electron microscopy (EM) shows deposits of granular osmiophilic material (GOM) in VSMC indentations or in the extracellular space in close vicinity to VSMCs [11], [12], [13]. Even though GOM was originally described in the CNS, it is now accepted that CADASIL is a systemic disease [13], [14], [15], [16], [17]; accordingly, GOM has also been identified in skin and muscle biopsies [4], [18], [19]. Over the past 12 years we had the opportunity to examine skin and muscle biopsies from several patients suspected to have CADASIL.…”

Section: Introductionmentioning

confidence: 99%

Role of Electron Microscopy in the Diagnosis of Cadasil Syndrome: A Study of 32 Patients

Morroni

Marzioni

Ragno³

et al. 2013

PLoS ONE

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Background and PurposeCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 gene mutations that result in vascular smooth muscle cell (VSMC) degeneration. Its distinctive feature by electron microscopy (EM) is granular osmiophilic material (GOM) detected in VSMC indentations and/or the extracellular space close to VSMCs. Reports of the sensitivity of EM in detecting GOM in biopsies from CADASIL patients are contradictory. We present data from 32 patients clinically suspected to have CADASIL and discuss the role of EM in its diagnosis in this retrospective study.MethodsSkin, skeletal muscle, kidney and pericardial biopsies were examined by EM; the NOTCH3 gene was screened for mutations. Skin and muscle biopsies from 12 patients without neurological symptoms served as controls.Results and DiscussionAll GOM-positive patients exhibited NOTCH3 mutations and vice versa. This study i) confirms that EM is highly specific and sensitive for CADASIL diagnosis; ii) extends our knowledge of GOM distribution in tissues where it has never been described, e.g. pericardium; iii) documents a novel NOTCH3 mutation in exon 3; and iv) shows that EM analysis is critical to highlight the need for comprehensive NOTCH3 analysis. Our findings also confirm the genetic heterogeneity of CADASIL in a small Italian subpopulation and emphasize the difficulties in designing algorithms for molecular diagnosis.

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“…Also, GOM was found on skin biopsy, which is diagnostic but can be negative. 5,6 Therefore, brain morphological examination still remains the most important tool in diagnosis of the disease, especially in sporadic cases.…”

Section: Introductionmentioning

confidence: 99%

CADASIL or CADVaSIL?

et al. 2004

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In the present study, morphological examination of patients from two unrelated Polish families with CADASIL was performed. Using light microscopy, there were evident changes characteristic to the disease. On electron microscopy, deposits of granular osmiophillic material (GOM) were found not only in cerebral arteries and veins but also in cerebral capillaries and vessels of the internal organs. These findings indicate that pathological process in CADASIL is generalized and involves also small vessels devoid of smooth muscle cells. Therefore, we propose to consider a replacement for the name CADASIL that better reflects the morphological picture of the disease like, for example, cerebral autosomal dominant vasculopathy with subcortical infarcts and leukoencephalopathy (CADVaSIL) or, to preserve the commonly known acronym, cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.

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Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications

Cited by 69 publications

References 22 publications

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

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

Role of Electron Microscopy in the Diagnosis of Cadasil Syndrome: A Study of 32 Patients

CADASIL or CADVaSIL?

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