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Non-syndromic thoracic aortic aneurysm: cellular and molecular insights.

ABSTRACT: Thoracic aortic aneurysm (TAA) develops silently and asymptomatically and is a major cause of mortality. TAA prevalence is greatly underestimated, it is usually diagnosed incidentally, and its treatment consists mainly of prophylactic surgery based on the aortic diameter. The lack of effective drugs and biological markers to identify and stratify TAAs by risk before visible symptoms results from scant knowledge of its pathophysiological mechanisms. Here we integrate the structural impairment affecting non-syndromic non-familial TAA with the main cellular and molecular changes described so far and consider how these changes are interconnected through specific pathways. The ultimate goal is to define much-needed novel markers of TAA, and so the potential of previously identified molecules to aid in early diagnosis/prognosis is also discussed. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

SUBMITTER: Martin-Blazquez A

PROVIDER: S-EPMC8251829 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Non-syndromic thoracic aortic aneurysm: cellular and molecular insights.

Martin-Blazquez Ariadna A Heredero Angeles A Aldamiz-Echevarria Gonzalo G Martin-Lorenzo Marta M Alvarez-Llamas Gloria G

The Journal of pathology 20210524 3

Thoracic aortic aneurysm (TAA) develops silently and asymptomatically and is a major cause of mortality. TAA prevalence is greatly underestimated, it is usually diagnosed incidentally, and its treatment consists mainly of prophylactic surgery based on the aortic diameter. The lack of effective drugs and biological markers to identify and stratify TAAs by risk before visible symptoms results from scant knowledge of its pathophysiological mechanisms. Here we integrate the structural impairment aff ...[more]

PMID: 33885146

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Project description:Thoracic aortic aneurysms result from dysregulated remodeling of the vascular extracellular matrix, which may occur as a result of altered resident cellular function. The present study tested the hypothesis that aortic fibroblasts undergo a stable change in cellular phenotype during thoracic aortic aneurysm formation.Primary murine aortic fibroblasts were isolated from normal and thoracic aortic aneurysm-induced aortas (4 weeks post induction with 0.5 mol/L CaCl(2) 15 minutes) by the outgrowth method. Normal and thoracic aortic aneurysm cultures were examined using a focused polymerase chain reaction array to determine fibroblast-specific changes in gene expression in the absence and presence of biological stimulation (endothelin-1, phorbol-12-myristate-13-acetate, angiotensin-II). The relative expression of 38 genes, normalized to 4 housekeeping genes, was determined, and genes displaying a minimum 2-fold increase/decrease or genes with significantly different normalized cycle threshold values were considered to have altered expression.At steady state, thoracic aortic aneurysm fibroblasts revealed elevated expression of several matrix metalloproteinases (Mmp2, Mmp11, Mmp14), collagen genes/elastin (Col1a1, Col1a2, Col3a1, Eln), and other matrix proteins, as well as decreased expression of Mmp3, Timp3, and Ltbp1. Moreover, gene expression profiles in thoracic aortic aneurysm fibroblasts were different than normal fibroblasts after equivalent biological stimuli.This study demonstrated for the first time that isolated primary aortic fibroblasts from thoracic aortic aneurysm-induced mice possess a unique and stable gene expression profile, and when challenged with biological stimuli, induce a transcriptional response that is different from normal aortic fibroblasts. Together, these data suggest that aortic fibroblasts undergo a stable phenotypic change during thoracic aortic aneurysm development, which may drive the enhancement of extracellular matrix proteolysis in thoracic aortic aneurysm progression.

Project description:BackgroundThoracic aortic aneurysms and dissections (TAAD) is a critical condition that often goes undiagnosed with fatal consequences. While majority of the cases are sporadic, more than 20% are inherited as a single gene disorder. The most common familial TAA is Marfan syndrome (MFS), which is primarily caused by mutations in fibrillin-1 (FBN1) gene. Patients with FBN1 mutations are at higher risk for dissection compared to other patients with similar size aneurysms.MethodsFifteen family members were genotyped using Affymetrix-10K genechips. A genome-wide association study was carried out using an autosomal dominant model of inheritance with incomplete penetrance. Mutation screening of all exons and exon-intron boundaries of FBN1 gene which reside near the peak Lod score was carried out by direct sequencing.ResultsThe index case presented with agonizing substernal pain and was found to have TAAD by transthoracic echocardiogram. The family history was significant for 3 first degree relatives with TAA. Nine additional family members were diagnosed with TAA by echocardiography examinations. The affected individuals had no syndromic features. A genome-wide analysis of linkage mapped the disease gene to a single locus on chromosome 15q21 with a peak Lod score of 3.6 at fibrillin-1 (FBN1) gene locus (odds ratio > 4000:1 in favour of linkage), strongly suggesting that FBN1 is the causative gene. No mutation was identified within the exons and exon-intron boundaries of FBN1 gene that segregated with the disease. Haplotype analysis identified additional mutation carriers who had previously unknown status due to borderline dilation of the ascending aorta.ConclusionsA familial non-syndromic TAAD is strongly associated with the FBN1 gene locus and has a malignant disease course often seen in MFS patients. This finding indicates the importance of obtaining detailed family history and echocardiographic screening of extended relatives of patients with non-syndromic TAAD to improve the outcome. In addition, association of non-syndromic TAAD with the Marfan disease gene locus poses the question whether secondary prevention strategies employed for Marfan syndrome patients should be applied to all patients with familial TAAD.

Dataset Information

Non-syndromic thoracic aortic aneurysm: cellular and molecular insights.

Publications

Non-syndromic thoracic aortic aneurysm: cellular and molecular insights.

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