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

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.

[Microangiopathy CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) - a chalange for general practitioner].

Small cerebral vessel disease is a relatively new group of angiopathies diagnosed more frequently thanks to common availability of neuroimaging. The most frequent and the most known disease which belongs to this group is CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Despite the name, it is a generalized small vessel disease, in which symptoms of brain damage dominate. The disease manifests as recurrent ischemic strokes, progressing dementia, migraine and mental disorders ­ symptoms which usually appear in 4-5 decade of life in patients without typical risk factors for vascular disease. In neuroimaging hyperintense changes and small ischemic foci disseminated in the cerebral white matter are seen. CADASIL is caused by mutations in the NOTCH 3 gene, which lead to the degeneration and loss of smooth muscle cells in small arteries. The disease is diagnosed on the basis of the result of the genetic test and microscopic examination of blood vessels in the material derived from a skin or skinmuscle biopsy. Since more and more frequently new techniques of neuroimaging reveal changes in the cerebral white matter - often asymptomatic or/ and mistakenly diagnosed as demyelinating lesions - only knowledge about CADASIL and other microangiopathies allows to avoid diagnostic errors.

Disturbed integrin expression in the vascular media in CADASIL.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited angiopathy characterized by degeneration and loss of vascular smooth muscle cells (VSMCs) of still unknown pathomechanism. Many functions of VSMCs, such as adhesion, apoptosis, contraction, differentiation, migration, and proliferation are determined by integrins - surface adhesion receptors involved in binding and interactions between cells and extracellular matrix (ECM). Since integrins play such an important role in VSMCs biology, disturbances in their expression may influence myocytes behavior and fate in CADASIL. In this study, we focused on the most important compounds of VSMCs integrins: subunits α4, ß1, and ß3 in an attempt to elucidate their immune expression in the arterial media of CADASIL patients. The immunohistochemistry revealed a decreased expression of integrin ß1 subunit (p < 0.001) but similar to the control expression of integrin subunits α4 and ß3. Decreased ß1 immunoreactivity was observed in capillary vessels, arterioles, and small arteries. The abnormal immune expression of integrin ß1 subunit was found even in microvessels without microscopically noted degenerative changes, which suggests that this is an early phenomenon in CADASIL. Since integrin ß1 subunit is a compound of 10 heterodimer integrin receptors, its disturbed expression may significantly influence VSMCs biology leading to myocytes degeneration and loss via anoikis - a type of apoptotic cell death due to loss or inappropriate cell adhesion to ECM.