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An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Ainscough, Alexander J 
Smith, Timothy J 
Haensel, Maike 
Rhodes, Christopher J 

Abstract

Pulmonary arterial hypertension (PAH) is an unmet clinical need. The lack of models of human disease is a key obstacle to drug development. We present a biomimetic model of pulmonary arterial endothelial-smooth muscle cell interactions in PAH, combining natural and induced bone morphogenetic protein receptor 2 (BMPR2) dysfunction with hypoxia to induce smooth muscle activation and proliferation, which is responsive to drug treatment. BMPR2- and oxygenation-specific changes in endothelial and smooth muscle gene expression, consistent with observations made in genomic and biochemical studies of PAH, enable insights into underlying disease pathways and mechanisms of drug response. The model captures key changes in the pulmonary endothelial phenotype that are essential for the induction of SMC remodelling, including a BMPR2-SOX17-prostacyclin signalling axis and offers an easily accessible approach for researchers to study pulmonary vascular remodelling and advance drug development in PAH.

Description

Keywords

Humans, Bone Morphogenetic Protein Receptors, Type II, Epoprostenol, Hypertension, Pulmonary, Pulmonary Arterial Hypertension, SOXF Transcription Factors

Journal Title

Commun Biol

Conference Name

Journal ISSN

2399-3642
2399-3642

Volume Title

5

Publisher

Springer Science and Business Media LLC
Sponsorship
British Heart Foundation (PG/19/19/34286, RE/18/4/34215, FS/17/64/33476)
Wellcome Trust (104931/Z/14/Z)
Biotechnology and Biological Sciences Research Council (BB/L015129/1)