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Open Access 01-12-2015 | Research

The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease

Authors: Maria-Magdalena Georgescu, Marco da Cunha Pinho, Timothy E. Richardson, Jose Torrealba, L. Maximilian Buja, Dianna M. Milewicz, Jack M. Raisanen, Dennis K. Burns

Published in: Acta Neuropathologica Communications | Issue 1/2015

Abstract

Introduction

Smooth muscle cell contraction is an essential function of arteries and relies on the integrity of the actin-myosin apparatus. The tissue-specific α2-smooth muscle actin, encoded by ACTA2, is predominantly expressed in vascular smooth muscle cells. ACTA2 mutations predispose to development of aortic aneurysms and early onset coronary and cerebrovascular disease. Based on arteriographic findings, a distinct cerebrovascular disease has been proposed for ACTA2 heterozygous patients carrying the R179H mutation.

Results

We present the first integrated analysis of a severely compromised patient with the R179H mutation and define the arterial pathology of ACTA2-related cerebrovascular disease. Histologically, striking morphological abnormalities were present in cerebral arteries of all sizes. Massive intimal smooth muscle cell proliferation, fragmentation of the elastic laminae and medial fibromuscular proliferation characterized large arteries whereas prominent vessel wall thickening, fibrosis and smooth muscle cell proliferation were unique changes in small arteries. The medial fibrosis and smooth muscle cell proliferation explain the characteristic radiologic appearance of “straight arteries” and suggest impaired function of mutant smooth muscle cells. Actin three-dimensional molecular modeling revealed critical positioning of R179 at the interface between the two strands of filamentous actin and destabilization of inter-strand bundling by the R179H mutation, explaining the severe associated phenotype.

Conclusions

In conclusion, these characteristic clinical and pathologic findings confirm ACTA2-related cerebrovascular disease as a new cerebrovascular disorder for which new therapeutic strategies need to be designed.

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Title: The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease
Authors: Maria-Magdalena Georgescu
Marco da Cunha Pinho
Timothy E. Richardson
Jose Torrealba
L. Maximilian Buja
Dianna M. Milewicz
Jack M. Raisanen
Dennis K. Burns
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-015-0262-7

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Springer Medicine

The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease

Abstract

Introduction

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Results

Conclusions

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