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Updated: Feb 18, 2026
Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro
Published on: May 10, 2021
Different Notch signaling in cells from calcified bicuspid and tricuspid aortic valves
A Kostina1, A Shishkova2, E Ignatieva2
1National Almazov Medical Research Centre, Saint-Petersburg, Russia; University of Verona, Verona, Italy; ITMO University, Institute of translational Medicine, St. Petersburg, Russia.
Insights
Early calcific aortic valve disease mechanisms differ between bicuspid and tricuspid valves. Notch signaling plays a distinct role in bicuspid aortic valve calcification initiation, impacting valve interstitial and endothelial cell responses.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Biomaterials Science
Background:
- Calcific aortic valve disease (CAVD) is a prevalent condition, often studied without differentiating between bicuspid and tricuspid aortic valve etiologies.
- Notch signaling is crucial for aortic valve development, and mutations in NOTCH1 are linked to bicuspid aortic valve (BAV) and calcification.
- Distinct disease progression dynamics between BAV and tricuspid aortic valve (TAV) suggest underlying mechanistic differences.
Purpose of the Study:
- To investigate and compare Notch-dependent mechanisms of aortic valve mineralization in bicuspid versus tricuspid aortic valve calcification.
- To determine if cellular responses to Notch activation differ between interstitial and endothelial cells derived from BAV and TAV.
Main Methods:
- Aortic valve interstitial cells (AVICs) and valve endothelial cells (VECs) were isolated from patients with calcific aortic stenosis (CAS) with either BAV or TAV.
- Quantitative PCR (qPCR) assessed Notch-related gene expression in AVICs.
- Discriminant analysis classified cell gene expression patterns; in vitro assays evaluated cellular sensitivity to pro-osteogenic stimuli and Notch activation.
Main Results:
- Gene expression patterns in AVICs from calcified BAVs formed a distinct group separate from calcified TAVs and controls.
- BAV-derived AVICs showed heightened sensitivity to pro-osteogenic stimuli and Notch activation, upregulating OPN, ALP, and POSTN.
- Notch-activated endothelial-to-mesenchymal transition (EndoMT) and HEY1/SLUG expression were more pronounced in BAV-derived VECs compared to TAV and healthy controls.
Conclusions:
- Early signaling events, specifically Notch-dependent mechanisms, initiating aortic valve calcification differ significantly between BAV and TAV patients.
- These findings highlight distinct cellular pathways involved in BAV calcification, suggesting potential for targeted therapeutic strategies.
Aims:
Calcific aortic valve disease is the most common heart valve disease in the Western world. Bicuspid and tricuspid aortic valve calcifications are traditionally considered together although the dynamics of the disease progression is different between the two groups of patients. Notch signaling is critical for bicuspid valve development and NOTCH1 mutations are associated with bicuspid valve and calcification. We hypothesized that Notch-dependent mechanisms of valve mineralization might be different in the two groups.
Methods And Results:
We used aortic valve interstitial cells and valve endothelial cells from patients with calcific aortic stenosis with bicuspid or tricuspid aortic valve. Expression of Notch-related genes in valve interstitial cells by qPCR was different between bicuspid and tricuspid groups. Discriminant analysis of gene expression pattern in the interstitial cells revealed that the cells from calcified bicuspid valves formed a separate group from calcified tricuspid and control cells. Interstitial cells from bicuspid calcified valves demonstrated significantly higher sensitivity to stimuli at early stages of induced proosteogenic differentiation and were significantly more sensitive to the activation of proosteogenic OPN, ALP and POSTIN expression by Notch activation. Notch-activated endothelial-to-mesenchymal transition and the corresponding expression of HEY1 and SLUG were also more prominent in bicuspid valve derived endothelial cells compared to the cells from calcified tricuspid and healthy valves.
Conclusion:
Early signaling events including Notch-dependent mechanisms that are responsible for the initiation of aortic valve calcification are different between the patients with bicuspid and tricuspid aortic valves.
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