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Updated: Jul 8, 2025
Scanning Electron Microscopy of Macerated Tissue to Visualize the Extracellular Matrix
Published on: June 14, 2016
Temporal expression and spatial distribution of the proteoglycan versican during cardiac fibrosis development
Athiramol Sasi1,2, Andreas Romaine1,2, Pugazendhi Murugan Erusappan1
1Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
Insights
Versican, a protein elevated in heart failure, plays a key role in cardiac fibrosis development. Its expression and cleavage increase during fibrosis, suggesting it
Area of Science:
- Cardiovascular Biology
- Extracellular Matrix Research
- Fibrosis Pathogenesis
Background:
- Cardiac fibrosis is a hallmark of heart disease, but its molecular drivers are unclear.
- Versican, an extracellular matrix proteoglycan, is implicated in heart failure.
- The precise role and localization of versican in cardiac fibrosis progression require further investigation.
Purpose of the Study:
- To investigate the temporal and spatial expression of versican and its cleavage fragment (DPEAAE) during cardiac fibrosis.
- To elucidate the role of versican in the development of cardiac fibrosis using a murine model and human patient samples.
Main Methods:
- Murine pressure overload model to induce cardiac fibrosis.
- Analysis of versican expression (V1 isoform) and collagen accumulation.
- Cardiac cell cultures stimulated with transforming growth factor beta and mechanical stretch.
- Assessment of versican cleavage fragment (DPEAAE) levels.
- Examination of versican and collagen mRNA in human cardiomyopathy samples.
Main Results:
- Versican (V1 isoform) expression preceded collagen accumulation post-pressure overload.
- Versican protein localized to the perivascular and interstitial spaces.
- Fibroblasts expressing collagen increased versican production.
- Transforming growth factor beta and mechanical stretch induced versican expression in vitro.
- Increased versican cleavage (DPEAAE fragment) occurred in late-stage fibrosis.
- Elevated versican and versican/collagen mRNA correlation found in human cardiomyopathies.
Conclusions:
- The temporal and spatial expression patterns of versican and its DPEAAE fragment suggest a significant role in cardiac fibrosis.
- Versican is an early responder and integral component of the fibrotic extracellular matrix in the heart.
- Targeting versican may offer a therapeutic strategy for cardiac fibrosis.
Abstract:
Cardiac fibrosis is a central pathological feature in several cardiac diseases, but the underlying molecular players are insufficiently understood. The extracellular matrix proteoglycan versican is elevated in heart failure and suggested to be a target for treatment. However, the temporal expression and spatial distribution of versican and the versican cleavage fragment containing the neoepitope DPEAAE in cardiac fibrosis remains to be elucidated. In this study, we have examined versican during cardiac fibrosis development in a murine pressure overload model and in patients with cardiomyopathies. We found that versican, mainly the V1 isoform, was expressed immediately after induction of pressure overload, preceding collagen accumulation, and versican protein levels extended from the perivascular region into the cardiac interstitium. In addition, we found increased production of versican by collagen expressing fibroblasts, and that it was deposited extensively in the fibrotic extracellular matrix during pressure overload. In cardiac cell cultures, the expression of versican was induced by the pro-fibrotic transforming growth factor beta and mechanical stretch. Furthermore, we observed that the proteolytic cleavage of versican (DPEAAE fragment) increased in the late phase of fibrosis development during pressure overload. In patients with hypertrophic and dilated cardiomyopathies, we found elevated levels of versican and a positive correlation between versican and collagen mRNA in the heart, as well as increased cleavage of full-length protein. Taken together, the temporal expression profile and the spatial distribution of both the full-length versican and the DPEAAE fragment observed in this study indicates a role for versican in development of cardiac fibrosis.
