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

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic vascular disease caused by Notch 3 gene mutations. On electron microscopy a specific granular osmiophilic material (GOM) is found surrounding the vascular smooth muscle cells. In 1993, we first proposed the use of skin biopsy to diagnose patients and to identify relatives of patients with CADASIL. We analyze here our experience with skin biopsies from 50 patients with CADASIL and compare the findings with those of 20 normal skin biopsy specimens. A morphometric analysis of skin vessel morphology on electron microscopy was performed by systematic measurements of several blood vessel diameters, as well as of areas of lumen, endothelial cell and smooth muscle cell cross-sectional areas, vessel wall area, arterial media and extracellular matrix areas. We found relative absence of stenosis but marked destruction of smooth muscle cells, resulting in decrease of vessel wall thickness and loss of extracellular matrix area, producing vessel wall weakness. Similar changes were also observed in brain arterioles from 5 patients with CADASIL. Our results suggest that hypotonicity of the arteriolar tree may constitute an important pathogenetic mechanism in CADASIL. Other than hypotonicity, the early and severe destruction of smooth muscle cells may potentially result in decreased secretion of vascular endothelial growth factor, loss of vascular permeability and damaging hemodynamic consequences. Blood vessel morphology of skin vessels correlated well with changes in brain arterioles. Vascular morphology in skin biopsy samples contributes to our understanding of the pathogenesis of CADASIL. It could be important to perform skin biopsies in future therapeutic trials of CADASIL as a direct measure of therapeutic effectiveness.