Vascular accumulation of the small leucine-rich proteoglycan decorin in CADASIL

Abstract

Small penetrating brain artery thickening is a major feature of cerebral autosomal dominant arteriopathy with subcortical infacts and leukoencephalopathy (CADASIL). Though affected fibrotic arteries of CADASIL have been shown to accumulate collagen, other components that compose pathological arterial walls remain incompletely characterized. We investigated the expression of decorin (DCN), the first collagen-binding small leucine rich proteoglycan identified, in CADASIL. DCN was markedly upregulated in pathologically affected leptomeningeal and small penetrating arteries in CADASIL and notably weaker in normal arteries from control brains. DCN protein was localized principally to the media and adventitia and only occasionally expressed in the intima. Immunoblotting of brain lysates showed a 3-fold increase of DCN in CADASIL brains (compared to controls). Messenger RNA encoding DCN was 5-fold increased in CADASIL. We conclude that DCN is the first identified proteoglycan to be identified in CADASIL arteries and may accumulate through transcriptional mechanisms. Additional studies are warranted to determine whether DCN localizes broadly to pathological small vessels in other cerebrovascular disorders.

Redistribution of Mature Smooth Muscle Markers in Brain Arteries in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

“…NOTCH3 ectodomain accumulation is a molecular hallmark of CADASIL arteries [5]. We have also previously described the accumulation of proteoglycans and collagens in the medial extracellular matrix of diseased CADASIL arteries [49–51]. Future studies should investigate what, if any, effect(s) these molecular changes could have on the expression of the in question.…”

The Small Leucine-Rich Proteoglycan BGN Accumulates in CADASIL and Binds to NOTCH3

“…The elevation of BGN transcripts in response to NOTCH3-Fc was blocked by rapamycin. Messenger RNA encoding additional components of pathological vessels, DCN [28] and COL4A1 [6], were also upregulated by incubation with NOTCH3 ectodomain. Stimulation of both DCN and COL4A1 message was also blocked by rapamycin.…”

“…In addition, two CADASIL brains from patients with ischemic stroke and dementia with the NOTCH3 mutations R141C and R153C were studied [28]; both of these patients were Caucasian males in their 60s who died of complications of the disease. All brains in the CADASIL group showed severe small vessel disease, with significant white matter hyperintensities on premortem MRI imaging.…”

“…Accumulation of DCN protein and mRNA was recently demonstrated in small penetrating arteries of CADASIL [28]. Strong expression of both collagen and DCN in brain arteries in CADASIL prompted us to hypothesize that BGN may also accumulate within thickened blood vessels in this disease.…”

Proteostasis in Cerebral Small Vessel Disease

“…TIMP3 and vitronectin were shown to colocalize with GOM deposits, to bind to Notch3 ECD in vitro and to also accumulate in brain vessels of a CADASIL mouse model. From these and other studies (Kast et al, 2014; Lee et al, 2014; Zhang et al, 2015), it became increasingly clear, that the accumulation of ECM proteins represents a critical step in CADASIL pathogenesis likely causing a dysregulation of ECM homeostasis and multifactorial toxicity (Joutel et al, 2016). To provide further support for this hypothesis in a larger cohort and with increased proteome depth, Zellner et al (2018) conducted label-free quantitative LC-MS/MS on brain vessels from six patients carrying five different Notch3 mutations and six age-matched healthy controls.…”