From silence to surge : illuminating the stealthy threat of aneurysms and dissections with the aid of cell models and insights into the genetic architecture

Perik, Mèlanie H.A.M.

Title

Author

Perik, Mèlanie H.A.M.

Abstract

Thoracic aortic wall weakening can lead to thoracic aortic aneurysms (TAAs) and life-threatening dissections and ruptures. Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by skeletal and cardiovascular features, including TAA(D)s. LDS is distinguished by features like hypertelorism, cleft palate or bifid uvula, widespread arterial tortuosity, and a predisposition for aneurysms throughout the arterial tree. This autosomal dominant disorder results from loss-of-function mutations in genes involved in the transforming growth factor-beta (TGFβ) signaling pathway. This thesis examines LDS type V (LDS-V), focusing on a p.(Asp263His) likely pathogenic variant in the TGFB3 gene. Mutations in TGFB3 typically result in milder symptoms with significant intra- and interfamilial phenotypic variability. By studying five distantly related families with this variant, a range of connective tissue and cardiovascular features, such as hypertrophic cardiomyopathy and valve abnormalities, was observed, but with limited aortic involvement. This suggests that additional factors may be required for aneurysm development in LDS-V patients. To further explore this, peripheral blood mononuclear cell-derived induced pluripotent stem cells (iPSCs) were differentiated into neural crest-derived vascular smooth muscle cells (VSMCs) to create a disease-specific model. Enhancements such as heparin stimulation during starvation were used to increase VSMC maturity and functional studies were optimized. Preliminary findings showed that VSMCs from LDS-V patients harboring the p.(Asp263His) variant exhibited a trend of reduced contractile marker expression, contractility and calcium flux compared to VSMCs from healthy controls. Furthermore, an upregulation of the (non-)canonical TGFβ pathway, was observed, indicating that this model successfully replicates aspects of LDS-V disease. Additionally, we tried to confirm the pathogenicity of the THSD4 gene, involved in fibrillin-1 matrix assembly and TGFβ regulation, in five additional THSD4 families. Despite its previous association with TAAs, we question the pathogenicity and classification of THSD4 variants due to the non-penetrance and non-segregation observed. Functional assays using the NC-VSMC model could further clarify the role of THSD4 in TAAD. Finally, spontaneous coronary artery dissection (SCAD) patients also show arterial wall weakening, potentially leading to severe outcomes. SCAD is linked to fibromuscular dysplasia (FMD) and occasionally to TAA(D) genes. Investigation of rare variants in known TAA(D) genes revealed that rare LDS variants impinge on SCAD risk, suggesting a role for dysregulated TGFβ signaling. These findings underscore the need for functional studies to better understand the impact of genetic variants on these diseases. IPSC-derived VSMCs offer a promising avenue for further research, risk assessment, and drug discovery, ultimately enhancing patient care.

Language

English

Publication

Antwerp : University of Antwerp, Faculty of Medicine and Health Sciences , 2024

DOI

10.63028/10067/2079210151162165141

Volume/pages

269 p.

Note

Supervisor: Van Laer, Lut [Supervisor]

Supervisor: Loeys, Bart [Supervisor]

Supervisor: Verstraeten, Aline [Supervisor]

Full text (open access)

The publisher created published version Available from 30.09.2025

Faculty/Department				Faculty of Medicine and Health Sciences Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences

Research group				Medical Genetics (MEDGEN)

Publication type				Doctoral thesis

Subject				Human medicine

Affiliation				Publications with a UAntwerp address

Identifier

c:irua:207921

Creation

12.09.2024

Last edited

04.10.2024

To cite this reference

https://hdl.handle.net/10067/2079210151162165141