3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension

Abstract

In pulmonary arterial hypertension (PAH), excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) causes vascular medial thickening. Medial thickening is a histopathological hallmark of pulmonary vascular remodeling, the central disease process driving PAH progression. Pulmonary vascular remodeling causes stenosis and/or obstruction of small pulmonary arteries. This leads to increased pulmonary vascular resistance, elevated pulmonary arterial pressure, and ultimately right heart failure. To improve the survival of PAH patients, which remains at approximately 60% at 3 years after diagnosis, the development of novel PAH-targeted drugs is desired. To this end, a detailed understanding of the mechanisms underlying excessive PASMC proliferation and the medial thickening that ensues is necessary. However, a lack of in vitro models that recapitulate medial thickening impedes our deeper understanding of the pathogenetic mechanisms involved. In the present study, we applied 3-dimensional (3D) cell culture technology to develop a novel in vitro model of the pulmonary artery medial layer using human PAH patient-derived PASMCs. The addition of platelet-derived growth factor (PDGF)-BB, a mitogen known to promote excessive PASMC proliferation in PAH, resulted in increased thickness of the 3D-PAH media tissues. Conversely, administration of the PDGF receptor inhibitor imatinib or other clinical PAH drugs inhibited this medial thickening-inducing effect of PDGF-BB. Altogether, by using 3D cell culture technology, we report the generation of an in vitro model of medial thickening in PAH, which had hitherto not been successfully modeled in vitro. This model is potentially useful for assessing the ability of candidate PAH drugs to suppress medial thickening.

Circular RNA‐HIPK3 regulates human pulmonary artery endothelial cells function and vessel growth by regulating microRNA‐328‐3p/STAT3 axis

“…PDGF can act on vascular endothelial cells as the incentive of PAH. 20 We used 10 ng/mL, 20 ng/mL, and 100 ng/mL PDGF (Sigma-Aldrich, Shanghai, China) to treat hPAECs for 4 h, then the hPAECs were collected for further experiments.…”

Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension

“…The plausibility of this gene contributing to PAH risk is further enhanced by cell-type-specific gene expression studies using single cell RNA-seq data, demonstrating high expression in endothelial cells within heart and lung tissue, a key site of disease potentiation in PAH [ 14 ]. Of interest, PDGFD presents an exciting drug-targeting candidate, with studies of the tyrosine kinase inhibitor imatinib, a known pharmacological inhibitor of PDGF signalling, demonstrating 15-fold reductions in PDGFD expression in cardiac tissue [ 47 ] and suppression of medial thickening via receptor inhibition in patient-derived in vitro PASMC models [ 48 ].…”

3D Tissue-Engineered Vascular Drug Screening Platforms: Promise and Considerations

“…We refer the reader to a recent review on 3D models of vascular pathologies (189,190). Systems were developed to model stenosis/atherosclerosis (191)(192)(193)(194), intimal hyperplasia, pulmonary hypertension (23), and thrombosis (195,196) (Figure 5). For example, Menon et al developed a 3D stenosis blood vessel model using a microfluidic chip composed of a cell culture channel and an air channel separated by a thin PDMS membrane which is deflected upwards by air to mimic stenotic plaque formation and model vascular constriction in atherosclerosis (193).…”

“…The authors suggested the use of this device as a point-of-care blood profiling device for diabetes and dyslipidimea (193). Morii et al have established a model for pulmonary hypertension by stimulating the thickening of a 3D media layer formed of human smooth muscle cells derived from pulmonary hypertension patients (23). Stimulation of medial thickening was achieved using platelet-derived growth factor BB, and the effect of pulmonary hypertension drugs was evaluated and confirmed to suppress medial thickening (23).…”

“…Morii et al have established a model for pulmonary hypertension by stimulating the thickening of a 3D media layer formed of human smooth muscle cells derived from pulmonary hypertension patients (23). Stimulation of medial thickening was achieved using platelet-derived growth factor BB, and the effect of pulmonary hypertension drugs was evaluated and confirmed to suppress medial thickening (23). Models of thrombosis have been also developed (195), including Thrombosis-on-a-Chip models (196).…”