Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by a cerebral non-atherosclerotic, nonamyloid angiopathy mainly affecting the small arteries penetrating the white matter. In the brain vessels of two patients with CADASIL, abnormal patches of granular osmiophilic material have recently been described. Here we report the observation of similar granular osmiophilic material within the vessel walls of muscle and skin biopsies from a 54-year-old woman belonging to a CADASIL family, who suffered from subcortical dementia with leukoencephalopathy demonstrated on neuroimaging. Postmortem examination disclosed changes of the vessel walls in all the organs chiefly leading to cerebral lesions. Ultrastructural study showed destruction of the vascular smooth muscle cells (VSMC) and the granular osmiophilic material already found in muscle and skin biopsies in this patient. Both changes were found all along the arterial tree. The findings of this study indicate that CADASIL is a systemic vascular disease involving arterial VSMC and that the lesions are different in each organ and vessel wall, depending on their fine structure. Moreover, it emphasizes that skin and muscle biopsies might be useful for diagnosis of and research into CADASIL.

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…The dense osmeophylic deposits form granules (10 to 15 nm in diameter) and occupy the middle layer of the vessel, extending to its adventitial layer, but sparing the vascular endothelium 21,27,28 . They are located near the cell membrane of VSMC, and stain positively for PAS (periodic acid Schiff ) -suggesting the presence of glycoproteins -and negatively for elastin and amyloid.…”

“…The VSMC, separated by granular material, are swollen and degenerated, and sometimes disappear and are replaced by collagen 29 . Vascular abnormalities characteristic of the brain of patients with CADASIL, like the GOM around the smooth muscle cells, are also common in the medial layer of arteries of other organs such as liver, spleen, heart, kidney, retina, muscles and skin, and even in large arteries such as aorta and carotid arteries 27,28 . Vascular lesions and accumulation of GOM may be detected in biopsies of muscle and nerve, and skin biopsies are commonly used for diagnostic purposes.…”

Characteristic Features of in vivo Skin Microvascular Reactivity in CADASIL

“…In CADASIL patients, an accumulation of the Notch3 protein is detected at the plasma membrane of VSMC, presumably related to altered clearance of the receptor (Joutel et al, 2001;Joutel and TournierLasserve 2002). In the vessel wall, the disease is characterized by a degeneration of VSMC and the presence of a granular osmiophilic material within the basement membrane (Joutel et al, 2000;Kalimo et al, 2002;Ruchoux et al, 1995).…”

Diagnosing Vascular Dementia by Skin Biopsy - Uniqueness of CADASIL

“…The mutations result in degeneration of vascular smooth muscle cells (VSMC), in which NOTCH3 is predominantly expressed in adult humans . The main pathological findings are accumulation of N3ECD on degenerating VSMCs as well as fibrosis and thickening of arterial walls, stenosis of arterioles and lacunar infarcts (Miao et al, 2004, Ruchoux et al, 1995. In electron microscopy (EM) the pathognomonic feature of CADASIL is accumulation of granular osmiophilic material (GOM) in indentations of the VSMCs or in the extracellular space in close vicinity to VSMCs (Baudrimont et al, 1993, Ruchoux et al, 1995.…”