Osteopontin and phospho-SMAD2/3 are associated with calcification of vessels in D-CAA, an hereditary cerebral amyloid angiopathy.

Laure Grand Moursel,Linda M Van Der Graaf,Marjolein Bulk,Louise Van Der Weerd,Willeke M.C Van Roon‐Mom

doi:10.1111/bpa.12721

Laure Grand Moursel, Linda M Van Der Graaf + Show 3 more

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https://doi.org/10.1111/bpa.12721

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Abstract

In severe forms of cerebral amyloid angiopathy (CAA) pathology, vascular calcification has been observed in the cerebral cortex, both in vivo on MRI and CT, and post‐mortem using histopathology. However, the pathomechanisms leading to calcification of CAA‐laden arteries are unknown. Therefore, we investigated the correlation between calcification of cortical arterioles and several potential modulators of vascular calcification using immunohistochemistry in a unique collection of brain material of patients with a hereditary form of CAA, namely hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D or D‐CAA).We show a topographical association of osteopontin (OPN) and TGFβ signaling factor phospho‐SMAD2/3 (pSMAD2/3) in calcified CAA vessel walls. OPN and pSMAD2/3 gradually accumulate in vessels prior to calcification. Moreover, we found that the vascular accumulation of Collagen 1 (Col1), OPN and pSMAD2/3 immunomarkers correlated with the CAA severity. This was independently of the vessel size, including capillaries in the most severe cases. We propose that calcification of CAA vessels in the observed HCHWA‐D cases may be induced by extracellular OPN trapped in the fibrotic Col1 vessel wall, independently of the presence of vascular amyloid.

Highlights

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an autosomal dominant genetic disorder caused by a missense mutation on chromosome 21 in the amyloid precursor protein (APP, NP_000475.1:p.Glu693Gln, known as APP E693Q) [29]
We investigated if vascular calcification in HCHWA-D is linked to expression of several factors known to promote calcification, independent of cerebral amyloid angiopathy (CAA) itself, namely transforming growth factor β (TGFβ), osteopontin (OPN) and collagen1 (Col1), as detailed below
This study investigated OPN and Collagen 1 (Col1) immunomarkers thought to promote calcification together with Aβ and pSMAD2/3 known immunomarkers associated with CAA severity, and proposes a mechanism of vascular calcification in D-CAA

Summary

Introduction

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an autosomal dominant genetic disorder caused by a missense mutation on chromosome 21 in the amyloid precursor protein (APP, NP_000475.1:p.Glu693Gln, known as APP E693Q) [29]. This so-called Dutch variant or D-CAA, is characterized by early onset cerebral amyloid angiopathy (CAA) defined by a progressive accumulation of Amyloid beta (Aβ) in the cerebral vasculature, resulting in acellular thickening of the vessel wall [1], leading to recurrent hemorrhagic strokes with midlife onset [15, 18]. It is unknown why some CAA-vessels exhibit calcifications, whereas other vessels with similar CAA load do not

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