Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Valzano, F.
Mosaicism of pulmonary arterial architecture and involvement of pulmonary hypertension associated alterations in vascular remodeling
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Crnkovic Slaven
- Kwapiszewska-Marsh Grazyna
- Altmetrics:
- Abstract:
- A central feature of progressive vascular remodeling is the establishment of an aberrant architecture of pulmonary arterial cells, characterized by altered thickening of the medial wall and dysfunctional endothelium. The understanding of how different cell populations contribute to this process is limited. Hence, we utilized single-cell RNA sequencing to provide insight into cellular composition changes within isolated pulmonary arteries (PAs) from pulmonary hypertension (PH) and donor lungs. Our results revealed the presence of a plethora of immune cells harboring in the PA and that remodeling skewed the balanced communication network between these cells and structural cells, such as fibroblasts, smooth muscle cells (SMC) and endothelial cells (EC). Transcriptionally distinct SMCs were enriched in diverse biological processes and could be divided into 4 major clusters: oxygen sensing (enriched in pericytes), contractile, synthetic, and fibroblast-like. Comparative analysis with murine PAs displayed a simpler architecture of PA wall, with only few SMC populations represented. Interestingly, medial wall of end-stage PA affected with pulmonary arterial hypertension (PAH) was associated with phenotypic shift of preexisting SMC populations and accumulation of synthetic SMCs in neointima. Endothelium, on the other hand, displayed three subsets of pulmonary arterial EC (PAEC). Of interest, these three subsets were equally represented in two forms of PH, namely pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with pulmonary fibrosis (PHPF). Comparative analysis of EC subpopulations in healthy and PH EC identified both a common genetic deregulation accompanying vascular remodeling as well as the development of disease-specific transcriptomic alterations in the three populations. Similarly to the medial layer, also murine intima layer was associated with a much simpler organization and only few EC populations detectable. The current study represents the first attempt to characterize the intricated architecture of PA and the molecular changes occurring with the establishment of vascular remodeling on a single population level.