Exploring disease-related changes in pulmonary arterial geometries and endothelial dysfunction in CTEPH
File(s)
Author(s)
Nicoleau, Salina
Type
Thesis
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe lung condition resulting from non-resolving pulmonary emboli, which cause vascular remodelling and elevated pulmonary arterial pressure. However, the exact role of alterations in arterial geometries and the resulting endothelial dysfunction in the development of CTEPH remains unclear.
Using 3D-printed in vitro models of pulmonary arterial stenoses found in CTEPH, the effects of arterial geometries and resulting changes in flow patterns on pulmonary endothelial function were characterised. Severe degrees of stenosis (60-80%) induced non-laminar, disturbed flow patterns in the post-stenotic dilatation region of the in vitro channels, which correlated with a loss of human pulmonary arterial endothelial cells (HPAECs) alignment and endothelial junctional integrity. Differential gene expression was observed in HPAECs cultured in various regions of the stenotic channels, with the levels of pro-inflammatory, pro-thrombotic and pro-angiogenic responses depending on the degree of stenosis. Additionally, increased platelet adhesion was observed in regions of disturbed flow.
The vascular stenosis models presented in this thesis highlight the importance of acute changes in vascular geometry on blood flow patterns, and the resulting impact on endothelial function and platelet aggregation. These CT scans-derived in vitro models have the potential to improve our understanding of pulmonary endothelial cells’ responses to vascular occlusion, not only in the context of CTEPH but also other diseases caused by stenosis, and demonstrate the potential of microfluidic platforms to bridge the gap between basic and clinical research.
Using 3D-printed in vitro models of pulmonary arterial stenoses found in CTEPH, the effects of arterial geometries and resulting changes in flow patterns on pulmonary endothelial function were characterised. Severe degrees of stenosis (60-80%) induced non-laminar, disturbed flow patterns in the post-stenotic dilatation region of the in vitro channels, which correlated with a loss of human pulmonary arterial endothelial cells (HPAECs) alignment and endothelial junctional integrity. Differential gene expression was observed in HPAECs cultured in various regions of the stenotic channels, with the levels of pro-inflammatory, pro-thrombotic and pro-angiogenic responses depending on the degree of stenosis. Additionally, increased platelet adhesion was observed in regions of disturbed flow.
The vascular stenosis models presented in this thesis highlight the importance of acute changes in vascular geometry on blood flow patterns, and the resulting impact on endothelial function and platelet aggregation. These CT scans-derived in vitro models have the potential to improve our understanding of pulmonary endothelial cells’ responses to vascular occlusion, not only in the context of CTEPH but also other diseases caused by stenosis, and demonstrate the potential of microfluidic platforms to bridge the gap between basic and clinical research.
Version
Open Access
Date Issued
2024-01
Date Awarded
2024-05
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Wojciak-Stothard, Beata
Gopalan, Deepa
McKinnon, Tom
Sponsor
Imperial College London
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)