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A Novel Stretching Platform for Applications in Cell and Tissue Mechanobiology
Published on: June 3, 2014
TRPV4 channel contributes to aortic root stiffening and atherosclerotic lesion development
Suneha G Rahaman1, Bidisha Dutta1, Shaik O Rahaman1
1University of Maryland, Department of Nutrition and Food Science, College Park, MD 20742.
Insights
Arterial stiffness contributes to atherosclerosis. Researchers identified mechanosensitive transient receptor potential vanilloid 4 (TRPV4) channels as a cellular sensor linking matrix stiffness to inflammation and fibrosis in atherosclerosis, suggesting TRPV4 as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Cellular Mechanotransduction
- Atherosclerosis Research
Background:
- Cardiovascular disease, particularly atherosclerosis, is a leading cause of mortality.
- Arterial stiffness is a recognized risk factor for atherosclerosis, but its underlying mechanisms remain unclear.
- Matrix stiffening influences inflammatory and fibrotic cellular activities, suggesting a role for cellular stiffness sensing in disease progression.
Purpose of the Study:
- To investigate the role of cellular stiffness sensing in the development of atherosclerosis.
- To identify the specific cellular mechanisms and molecular players involved in linking matrix stiffening to atherosclerotic pathology.
- To explore transient receptor potential vanilloid 4 (TRPV4) channels as a potential stiffness sensor in the context of atherosclerosis.
Main Methods:
- Utilized human aortic tissues and a murine atherosclerosis model.
- Employed atomic force microscopy (AFM) to analyze cellular mechanical properties.
- Investigated the influence of matrix stiffness on macrophage and fibroblast activation and inflammatory gene expression.
Main Results:
- Identified mechanosensitive transient receptor potential vanilloid 4 (TRPV4) channels as a key cellular stiffness sensor.
- Demonstrated that TRPV4 channels regulate macrophage and fibroblast activation, inflammation, and fibrosis.
- Established a link between matrix stiffening, cellular mechanosensing via TRPV4, and the progression of atherosclerosis.
Conclusions:
- TRPV4 channels act as a cellular sensor that translates matrix stiffness into inflammatory and fibrotic responses in atherosclerosis.
- A positive feedback loop exists where inflammation, fibrosis, and tissue stiffening reinforce each other, with macrophages playing a central role.
- Targeting TRPV4 presents a potential therapeutic strategy for preventing or mitigating atherogenesis.
Abstract:
Cardiovascular disease is the number one cause of death in the developed world and atherosclerosis, a chronic arterial disease, is the most dominant underlying pathology. Epidemiologic and experimental studies suggest that arterial stiffness is a risk factor for atherosclerosis. However, there has been surprisingly limited development in mechanistic understanding of the generation of arterial stiffness and little progress in understanding the mechanisms by which matrix stiffening drives the development of atherosclerosis. Various proinflammatory and fibrotic activities of macrophages and fibroblasts, such as migration, inflammatory gene expression, and myofibroblast activation, are influenced by matrix stiffness. This influence suggests that aorta stiffening may regulate atherosclerosis via a cellular stiffness sensor. Our research indicates that mechanosensitive transient receptor potential vanilloid 4 (TRPV4) channels control inflammation and fibrosis in other organs and regulate macrophage and fibroblast activation, implicating TRPV4 as a potential stiffness sensor in atherosclerosis. This suggests a cycle where inflammation, fibrosis, and tissue stiffening reinforce each other, with macrophages playing a key role. Here, we identify a cellular stiffness sensor linking matrix stiffness and atherosclerosis using human aortic tissues, a murine atherosclerosis model, and atomic force microscopy (AFM) analysis. This novel finding suggests that targeting TRPV4 could be a selective strategy to prevent or suppress atherogenesis.
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