This PhD thesis investigates the pathobiology of pulmonary arterial hypertension (PAH), a rare and life-threatening disease characterized by progressive narrowing and stiffening of the small pulmonary arteries. This vascular remodeling increases resistance in the pulmonary vasculation, ultimately resulting in right ventricular hypertrophy and right heart failure. Despite advances in treatment, current therapies primarily alleviate symptoms and do not halt or reverse disease progression.
A central aim of this thesis is to understand why PAH develops in only a subset of individuals, even among those carrying known genetic risk factors such as mutations in the BMPR2 gene. To address this question, the work investigates the hypothesis that PAH arises through a multi-hit mechanism, in which genetic susceptibility interacts with environmental or cellular stressors including inflammation, hypoxia, and altered hemodynamic forces.
The research focuses on the TGF-β...
Show moreThis PhD thesis investigates the pathobiology of pulmonary arterial hypertension (PAH), a rare and life-threatening disease characterized by progressive narrowing and stiffening of the small pulmonary arteries. This vascular remodeling increases resistance in the pulmonary vasculation, ultimately resulting in right ventricular hypertrophy and right heart failure. Despite advances in treatment, current therapies primarily alleviate symptoms and do not halt or reverse disease progression.
A central aim of this thesis is to understand why PAH develops in only a subset of individuals, even among those carrying known genetic risk factors such as mutations in the BMPR2 gene. To address this question, the work investigates the hypothesis that PAH arises through a multi-hit mechanism, in which genetic susceptibility interacts with environmental or cellular stressors including inflammation, hypoxia, and altered hemodynamic forces.
The research focuses on the TGF-β superfamily, which plays a crucial role in regulating vascular homeostasis. By combining established experimental models with newly developed microfluidic “vessel-on-a-chip” systems that mimic physiological blood flow, this thesis examines how chronic biochemical and mechanical stress disrupts endothelial cell function. The findings demonstrate that inflammatory signaling can promote endothelial-to-mesenchymal transition (EndMT), a process contributing to pathological vascular remodeling. In addition, potential biomarkers such as Activin A are identified as early indicators of disease imbalance. Collectively, this work advances our understanding of PAH pathogenesis and highlights new opportunities for early detection and targeted therapeutic intervention.
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