VEGFB Gene Therapy Reverses Heart Aging in Mice
Gene therapy targeting VEGFB restored heart function and reduced fibrosis in aged mice, offering new therapeutic hope.
Summary
Researchers used gene therapy to overexpress VEGFB186 in 18-month-old mice, successfully reversing key aspects of cardiac aging. The treatment prevented age-related diastolic dysfunction, reduced heart fibrosis, and restored nerve fiber density. While VEGFB induced some cardiac hypertrophy, this appeared compensatory rather than harmful. The therapy worked by activating the STAT3 pathway and improving heart rate variability. These findings suggest VEGFB could become a promising therapeutic target for combating age-related heart decline in humans.
Detailed Summary
Heart disease remains the leading cause of death globally, with aging being a primary risk factor. As populations age, understanding and treating age-related cardiac decline becomes increasingly critical. This study investigated whether VEGFB (vascular endothelial growth factor B) gene therapy could reverse cardiac aging.
Researchers first discovered that VEGFB expression, particularly the soluble VEGFB186 isoform, significantly declines in both aged mouse and human hearts. To test therapeutic potential, they used AAV9-mediated gene transfer to overexpress VEGFB186 in 18-month-old male mice (equivalent to elderly humans).
The results were striking. VEGFB186 overexpression prevented age-induced diastolic dysfunction - the heart's inability to properly relax and fill with blood. The treatment also reduced cardiac fibrosis, the harmful scarring that stiffens heart tissue with age. Additionally, it restored both sympathetic and sensory nerve fiber density and increased heart rate variability, indicating improved cardiac autonomic function.
While VEGFB186 treatment did induce cardiac hypertrophy (heart enlargement), detailed analysis revealed this was compensatory rather than pathological. The therapy corrected the elevated cardiomyocyte length-to-width ratio seen in aged hearts, suggesting beneficial remodeling. Single-cell RNA sequencing identified upregulation of the STAT3 signaling pathway as a key mechanism.
These findings demonstrate that targeted VEGFB gene therapy can partially reverse multiple age-related cardiac pathologies. The approach offers a potential new therapeutic avenue for combating cardiac aging, though human trials would be needed to confirm safety and efficacy.
Key Findings
- VEGFB186 gene therapy prevented age-related diastolic dysfunction in elderly mice
- Treatment reduced cardiac fibrosis and restored nerve fiber density in aged hearts
- Therapy improved heart rate variability and corrected pathological cardiomyocyte remodeling
- VEGFB works through STAT3 pathway activation to promote beneficial cardiac changes
- VEGFB expression naturally declines with age in both mouse and human hearts
Methodology
Researchers used AAV9-mediated gene transfer to overexpress VEGFB186 in 18-month-old male C57Bl/6J mice. They assessed cardiac function through echocardiography, analyzed tissue through histology and single-nucleus RNA sequencing, and measured nerve fiber density and heart rate variability.
Study Limitations
The study was conducted only in male mice, limiting generalizability. VEGFB treatment induced cardiac hypertrophy, which requires careful monitoring. Long-term safety and optimal dosing strategies need further investigation before human application.
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