期刊
CARDIOVASCULAR ENGINEERING AND TECHNOLOGY
卷 13, 期 3, 页码 481-494出版社
SPRINGER
DOI: 10.1007/s13239-021-00586-z
关键词
Calcific aortic valve disease; Alpha smooth muscle actin; Glycosaminoglycan; Endothelial; Hyaluronic acid
资金
- National Science Foundation [CMMI 1436173, CMMI 1919438]
- Binghamton University Clifford D. Clark Diversity Fellowship
The study demonstrated a comprehensive model of aortic valve disease, including endothelial cells, interstitial cells, and a stiff and disease-like extracellular matrix. In vitro models of both healthy and diseased valves can help understand the mechanisms of CAVD pathogenesis and serve as a model for testing novel therapeutics.
Purpose Calcific aortic valve disease (CAVD), has been characterized as a cascade of cellular changes leading to leaflet thickening and valvular calcification. In diseased aortic valves, glycosaminoglycans (GAGs) normally found in the valve spongiosa migrate to the collagen I-rich fibrosa layer near calcified nodules. Current treatments for CAVD are limited to valve replacement or drugs tailored to other cardiovascular diseases. Methods Porcine aortic valve interstitial cells and porcine aortic valve endothelial cells were seeded into collagen I hydrogels of varying initial stiffness or initial stiffness-matched collagen I hydrogels containing the glycosaminoglycans chondroitin sulfate (CS), hyaluronic acid (HA), or dermatan sulfate (DS). Assays were performed after 2 weeks in culture to determine cell gene expression, protein expression, protein secretion, and calcification. Multiple regression analyses were performed to determine the importance of initial hydrogel stiffness, GAGs, and the presence of endothelial cells on calcification, both with and without osteogenic medium. Results High initial stiffness hydrogels and osteogenic medium promoted calcification, while for DS or HA the presence of endothelial cells prevented calcification. CS was found to increase the expression of pro-calcific genes, increase activated myofibroblast protein expression, induce the secretion of collagen I by activated interstitial cells, and increase calcified nodule formation. Conclusion This study demonstrates a more complete model of aortic valve disease, including endothelial cells, interstitial cells, and a stiff and disease-like ECM. In vitro models of both healthy and diseased valves can be useful for understanding the mechanisms of CAVD pathogenesis and provide a model for testing novel therapeutics.
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