Activation of endothelial β-catenin signaling induces heart failure

Area of Science:

• Cardiovascular Biology
• Molecular and Cellular Biology
• Endothelial Cell Signaling

Background:

• Canonical Wnt/β-catenin signaling is crucial for angiogenesis but its other roles in endothelial cells are unclear.
• Endothelial cell dysfunction contributes to various cardiovascular diseases, including heart failure.

Purpose of the Study:

• To investigate the role of sustained Wnt/β-catenin signaling activation in endothelial cells on cardiac function.
• To elucidate the underlying molecular mechanisms linking endothelial Wnt/β-catenin signaling to cardiac dysfunction.

Main Methods:

• Utilized a conditional gain-of-function mouse model (Bmx/CA mice) with activated β-catenin in arterial endothelial cells.
• Assessed cardiac function, mortality, and cardiac morphology via electron microscopy.
• Analyzed endothelial neuregulin 1 (Nrg1) expression and cardiac ErbB signaling pathways.

Main Results:

• Sustained Wnt/β-catenin activation in endothelial cells led to progressive cardiac dysfunction and 100% mortality in Bmx/CA mice.
• Observed T-tubule dilatation and mitochondrial degeneration in cardiomyocytes, mirroring changes seen with suppressed neuregulin-ErbB signaling.
• Demonstrated suppressed endothelial Nrg1 and cardiac ErbB signaling in Bmx/CA mice, which was reversed by recombinant neuregulin administration.

Conclusions:

• Sustained endothelial Wnt/β-catenin signaling activation causes heart failure by suppressing the neuregulin-ErbB pathway.
• The Wnt/β-catenin/NRG axis in cardiac endothelial cells represents a potential therapeutic target for heart failure.