A group of researchers from the UK developed a microfluidic model for the study of pulmonary vascular remodeling that could facilitate drug development in pulmonary arterial hypertension (PAH).

“We present an organ-on-chip model of vascular endothelial and smooth muscle cell interactions that permits the study of dynamic changes in molecular and functional cell phenotype under physiological flow conditions in response to key factors linked to the development of PAH, such as BMPR2 silencing and hypoxia,” the researchers explained in Communications Biology.

Using the model, the researchers showed that ambrisentan (Letairis®), an endothelin receptor antagonist, AZD5153, an inhibitor of the bromodomain-containing protein 4, and imatinib mesylate (Gleevec®) could inhibit the proliferation of pulmonary artery smooth muscle cells (PASMCs). The therapeutic effects of ambrisentan and AZD5153 were observed in inducible microfluidic models featuring BMPR2-deficient human pulmonary artery endothelial cells and patient-derived endothelial colony-forming cells.


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The organ-on-chip model captured key changes in the pulmonary endothelial cell phenotype required for the induction of smooth muscle cells remodeling. The researchers identified endothelial SOX17 as a regulator of PASMC proliferation and found that its loss induced PASMC proliferation, an effect probably mediated by prostacyclin synthase and prostacyclin. Hence, the results suggest a role for the BMPR2-SOX17-prostacyclin signaling axis in smooth muscle cell remodelling in PAH.

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Bioinformatic analysis of differential gene expression in HPASMC cocultured with BMPR2-deficient human pulmonary artery endothelial cells in the organ-on-chip model showed enrichment in disease-specific phenotypes associated with angiogenesis, apoptosis, inflammation, vasoconstriction, and transforming growth factor β signaling.

Moreover, the study highlighted a microfluidic gene signature of vascular responses associated with PAH, which showed a substantial overlap with transcriptomic data. For instance, BMPR2-deficient human pulmonary artery endothelial cells showed reduced expression of transforming growth factor β family members, nitric oxide bioavailability enzymes, arterial identity factors, and regulators of angiogenesis, proliferation, and endothelial sprouting behavior.

Reference

Ainscough AJ, Smith TJ, Haensel M, et al. An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis. Commun Biol. 2022;5(1):1192. doi:10.1038/s42003-022-04169-z