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The Assembly and Application of 'Shear Rings': A Novel Endothelial Model for Orbital, Unidirectional and Periodic Fluid Flow and Shear Stress
Published on: October 31, 2016
Shear-Sensitive Genes in Aortic Valve Endothelium
Joan Fernández Esmerats1, Jack Heath1, Hanjoong Jo1
1Department of Biomedical Engineering, Emory University and Georgia Institute of Technology , Atlanta, Georgia .
Insights
Calcific aortic valve disease (CAVD) mechanisms are unclear, hindering non-surgical treatments. Understanding valve endothelium mechanosensing and signaling pathways is crucial for developing future therapies to avoid surgery.
Area of Science:
- Cardiovascular Biology
- Mechanobiology
- Endothelial Cell Signaling
Background:
- Calcific aortic valve disease (CAVD) lacks effective non-surgical treatments due to poorly understood underlying mechanisms.
- The aortic valve endothelium normally adapts to hemodynamic forces, but this adaptation is impaired in CAVD, leading to dysfunction and inflammation.
Purpose of the Study:
- To review the role of mechanical forces, mechanosensors, and signaling pathways in the aortic valve endothelium in the context of CAVD.
- To highlight the current understanding of how mechanical stimuli influence cellular phenotype and contribute to CAVD pathogenesis.
Main Methods:
- Review of existing literature on valvular structure, mechanobiology, and endothelial cell signaling in CAVD.
- Exploration of key signaling pathways including TGF-β, Wnt/β-catenin, NADPH oxidase, and microRNA regulation.
Main Results:
- Mechanical forces are sensed by endothelial mechanosensors, triggering downstream signaling cascades.
- Mechanosensitive genes are upregulated, altering cellular phenotype and promoting inflammation and CAVD.
- NADPH oxidase, reactive oxygen species/nitrogen species, and microRNAs play significant roles in the cellular response to mechanical stimuli.
Conclusions:
- A deeper understanding of aortic valve endothelium mechanobiology is essential for developing novel therapeutic strategies for CAVD.
- Future research focusing on these mechanisms could lead to treatments that prevent or reverse valve calcification, avoiding surgical intervention.
Significance:
Currently, calcific aortic valve disease (CAVD) is only treatable through surgical intervention because the specific mechanisms leading to the disease remain unclear. In this review, we explore the forces and structure of the valve, as well as the mechanosensors and downstream signaling in the valve endothelium known to contribute to inflammation and valve dysfunction.
Recent Advances:
While the valvular structure enables adaptation to dynamic hemodynamic forces, these are impaired during CAVD, resulting in pathological systemic changes. Mechanosensing mechanisms-proteins, sugars, and membrane structures-at the surface of the valve endothelial cell relay mechanical signals to the nucleus. As a result, a large number of mechanosensitive genes are transcribed to alter cellular phenotype and, ultimately, induce inflammation and CAVD. Transforming growth factor-β signaling and Wnt/β-catenin have been widely studied in this context. Importantly, NADPH oxidase and reactive oxygen species/reactive nitrogen species signaling has increasingly been recognized to play a key role in the cellular response to mechanical stimuli. In addition, a number of valvular microRNAs are mechanosensitive and may regulate the progression of CAVD.
Critical Issues:
While numerous pathways have been described in the pathology of CAVD, no treatment options are available to avoid surgery for advanced stenosis and calcification of the aortic valve. More work must be focused on this issue to lead to successful therapies for the disease.
Future Directions:
Ultimately, a more complete understanding of the mechanisms within the aortic valve endothelium will lead us to future therapies important for treatment of CAVD without the risks involved with valve replacement or repair. Antioxid. Redox Signal. 25, 401-414.
