Disturbed integrin expression in the vascular media in CADASIL

Dziewulska, Dorota; Nycz, Ewelina

doi:10.5114/fn.2016.64816

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…Such rounded appearance is characteristic of detached cells which are devoid of physical influences from ECM. Moreover, our previous study revealed disturbed expression of integrin subunit β-1 in CADASIL vessels that my lead to myocytes detachment from ECM [3]. This finding as well as the results reported by other authors suggests that degeneration and loss of VSMC can be secondary to pro-life or protecting signals originating from ECM.…”

Section: Introductionsupporting

confidence: 70%

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Changes in the Vascular Extracellular Matrix as a Potential Cause of Myocyte Loss via Anoikis in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Dziewulska¹,

Nycz²,

Rajczewska-Oleszkiewicz³

2017

J Clin Exp Pathol

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Objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a generalized vasculopathy caused by mutations in the NOTCH3 gene, leading to degeneration and loss of vascular smooth muscle cells (VSMC). The relationship between NOTCH 3 mutations and VSMC death is unknown. One possible cause of myocyte deficit may be anoikis, a special type of apoptosis due to loss or inappropriate cell adhesion to extracellular matrix. Method:To verify this hypothesis we examined immune expression of main compounds of vascular extracellular matrix (laminin, fibronectin and collagen IV) and selected metallo proteinases (MMP-2, MMP-3, and MMP-9) in cerebral, skin and skeletal muscle arterial vessels in autopsy material and biopsy specimens of CADASIL patients. Results:The immmune reactions revealed decreased expression of laminin and increased expression of collagen IV and fibronectin in arterial vessels. Moderately intense immune reactivity to MMP-9 and MMP-2 was present while immune reactivity to MMP-3 was absent. Conclusion:Quantitative and qualitative changes in vascular extracellular matrix found in CADASIL vessels may lead to VSMC loss via anoikis pathway.

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Section: Introductionsupporting

confidence: 70%

“…The diagnosis of CADASIL was established on the basis of ultra-structural criteria, i.e., the presence of pathognomonic for the disease GOM deposits in vessel walls [4], and in the majority of cases was additionally confirmed by genetic studies. Clinical details of the examined CADASIL material are presented in our previous paper [3].…”

Section: Methodsmentioning

confidence: 99%

Changes in the Vascular Extracellular Matrix as a Potential Cause of Myocyte Loss via Anoikis in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Dziewulska¹,

Nycz²,

Rajczewska-Oleszkiewicz³

2017

J Clin Exp Pathol

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“…Affected myocytes acquire variable nuclear sizes and shapes with abnormal chromatin appearance [ 12 ] that is related to the stress caused in the endoplasmic reticulum (ER) by accumulation of mutant NOTCH3 extracellular domain [ 36 , 56 ]. Consistent with the degeneration of VSMCs, decreased expression of integrin beta1 subunit and beta1 immunoreactivity were reported in small arteries, arterioles and capillaries in CADASIL [ 11 ].…”

Section: Introductionsupporting

confidence: 66%

ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics

Panahi

Hase

Gallart‐Palau

et al. 2023

acta neuropathol commun

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Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 mutations. Typical CADASIL is characterised by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small arteries. Arteriolar vascular smooth muscle cells (VSMCs) are the key target in CADASIL, but the potential mechanisms involved in their degeneration are still unclear. Focusing on cerebral microvessels in the frontal and anterior temporal lobes and the basal ganglia, we used advanced proteomic and immunohistochemical methods to explore the extent of inflammatory and immune responses in CADASIL subjects compared to similar age normal and other disease controls. There was variable loss of VSMC in medial layers of arteries in white matter as well as the cortex, that could not be distinguished whether NOTCH3 mutations were in the epidermal growth factor (EGFr) domains 1–6 or EGFr7-34. Proteomics of isolated cerebral microvessels showed alterations in several proteins, many associated with endoplasmic reticulum (ER) stress including heat shock proteins. Cerebral vessels with sparsely populated VSMCs also attracted robust accrual of perivascular microglia/macrophages in order CD45+ > CD163+ > CD68+cells, with > 60% of vessel walls exhibiting intercellular adhesion molecule-1 (ICAM-1) immunoreactivity. Functional VSMC cultures bearing the NOTCH3 Arg133Cys mutation showed increased gene expression of the pro-inflammatory cytokine interleukin 6 and ICAM-1 by 16- and 50-fold, respectively. We further found evidence for activation of the alternative pathway of complement. Immunolocalisation of complement Factor B, C3d and C5-9 terminal complex but not C1q was apparent in ~ 70% of cerebral vessels. Increased complement expression was corroborated in > 70% of cultured VSMCs bearing the Arg133Cys mutation independent of N3ECD immunoreactivity. Our observations suggest that ER stress and other cellular features associated with arteriolar VSMC damage instigate robust localized inflammatory and immune responses in CADASIL. Our study has important implications for immunomodulation approaches to counter the characteristic arteriopathy of CADASIL.

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“…They have lost their normal circumferential orientation in arterial walls and are not closely packed but separated from each other. Such isolated myocytes are round‐shaped which suggests their loss of adhesion to extracellular matrix . Ultrastructural studies of VSMCs showed their vacuolization, enlarged mitochondria, and a presence of deposits of granular osmiophilic material (GOM) within indentations of the cell membrane or in the tunica media.…”

Section: Introductionmentioning

confidence: 99%

Nuclear abnormalities in vascular myocytes in cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Dziewulska

Nycz

Rajczewska-Oleszkiewicz

et al. 2018

Neuropathology

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Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a stroke and dementia syndrome with degeneration and loss of vascular smooth muscle cells (VSMCs). The disease is due to mutations in NOTCH3 playing an important role in VSMC differentiation, proliferation and apoptosis. Searching for a possible cause of VSMC dysfunction in CADASIL, we investigated morphology and proliferative activity the affected myocytes. In material from autopsy brains and skin‐muscle biopsies of patients with CADASIL diagnosis, assessment of VSMCs in arterial vessels at the level of light and electron microscopy was performed. Proliferative activity of VSMCs was evaluated in immune reactions to proliferative markers: proliferating cell nuclear antigen, and cyclins B1 and D. In CADASIL, abnormal morphology of VSMC nuclei was observed in 18.1%, 11.5%, and 6.9% of the cerebral, skin, and skeletal muscle vessels, respectively. The affected myocytes showed variability in nuclear size, irregularity in nuclear shape, and abnormal chromatin appearance. Frequently, double nuclei of equal size or micronuclei were observed. Sometimes, even multinuclear myocytes were found. In some of the nuclei immune reactions to the examined proliferative markers were positive. Aberrant structure and number of VSCM nuclei, and their immunoreactivity to proliferative markers suggest mitotic instability of vascular myocytes in CADASIL. We speculate that mutant NOTCH3 which is unable to control properly VSMC proliferation, and may be responsible for their premature or inappropriate entry into mitosis, irreversible arrest of the cell cycle, senescence or degeneration and loss.

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Disturbed integrin expression in the vascular media in CADASIL

Abstract: A b s t r a c t CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inher-

Cited by 7 publications

References 25 publications

Changes in the Vascular Extracellular Matrix as a Potential Cause of Myocyte Loss via Anoikis in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Changes in the Vascular Extracellular Matrix as a Potential Cause of Myocyte Loss via Anoikis in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics

Nuclear abnormalities in vascular myocytes in cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

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