Pulmonary Vascular Platform Models the Effects of Flow and Pressure on Endothelial Dysfunction in BMPR2 Associated Pulmonary Arterial Hypertension
Autor: | Shannon Faley, Reid W. D’Amico, James West, Ha-na Shim, Leon M. Bellan, Vineet Agrawal, Joanna R. Prosser |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Endothelium Pulsatile flow 030204 cardiovascular system & hematology Cell morphology Catalysis endothelial dysfunction Inorganic Chemistry lcsh:Chemistry 03 medical and health sciences 0302 clinical medicine Arteriole medicine.artery pulmonary arterial hypertension disease modeling medicine Physical and Theoretical Chemistry Endothelial dysfunction Molecular Biology lcsh:QH301-705.5 Spectroscopy Associated Pulmonary Arterial Hypertension Lung Chemistry Organic Chemistry General Medicine medicine.disease Computer Science Applications BMPR2 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) lcsh:QD1-999 |
Zdroj: | International Journal of Molecular Sciences, Vol 19, Iss 9, p 2561 (2018) International Journal of Molecular Sciences Volume 19 Issue 9 |
ISSN: | 1422-0067 |
Popis: | Endothelial dysfunction is a known consequence of bone morphogenetic protein type II receptor (BMPR2) mutations seen in pulmonary arterial hypertension (PAH). However, standard 2D cell culture models fail to mimic the mechanical environment seen in the pulmonary vasculature. Hydrogels have emerged as promising platforms for 3D disease modeling due to their tunable physical and biochemical properties. In order to recreate the mechanical stimuli seen in the pulmonary vasculature, we have created a novel 3D hydrogel-based pulmonary vasculature model (&ldquo artificial arteriole&rdquo ) that reproduces the pulsatile flow rates and pressures seen in the human lung. Using this platform, we studied both Bmpr2R899X and WT endothelial cells to better understand how the addition of oscillatory flow and physiological pressure influenced gene expression, cell morphology, and cell permeability. The addition of oscillatory flow and pressure resulted in several gene expression changes in both WT and Bmpr2R899X cells. However, for many pathways with relevance to PAH etiology, Bmpr2R899X cells responded differently when compared to the WT cells. Bmpr2R899X cells were also found not to elongate in the direction of flow, and instead remained stagnant in morphology despite mechanical stimuli. The increased permeability of the Bmpr2R899X layer was successfully reproduced in our artificial arteriole, with the addition of flow and pressure not leading to significant changes in permeability. Our artificial arteriole is the first to model many mechanical properties seen in the lung. Its tunability enables several new opportunities to study the endothelium in pulmonary vascular disease with increased control over environmental parameters. |
Databáze: | OpenAIRE |
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