Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle
Jeffrey S Bonner1, Louise Lantier, Clinton M Hasenour
1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. jeffrey.s.bonner@vanderbilt.edu
Abstract:
Muscle insulin resistance is associated with a reduction in vascular endothelial growth factor (VEGF) action and muscle capillary density. We tested the hypothesis that muscle capillary rarefaction critically contributes to the etiology of muscle insulin resistance in chow-fed mice with skeletal and cardiac muscle VEGF deletion (mVEGF(-/-)) and wild-type littermates (mVEGF(+/+)) on a C57BL/6 background. The mVEGF(-/-) mice had an ~60% and ~50% decrease in capillaries in skeletal and cardiac muscle, respectively. The mVEGF(-/-) mice had augmented fasting glucose turnover. Insulin-stimulated whole-body glucose disappearance was blunted in mVEGF(-/-) mice. The reduced peripheral glucose utilization during insulin stimulation was due to diminished in vivo cardiac and skeletal muscle insulin action and signaling. The decreased insulin-stimulated muscle glucose uptake was independent of defects in insulin action at the myocyte, suggesting that the impairment in insulin-stimulated muscle glucose uptake was due to poor muscle perfusion. The deletion of VEGF in cardiac muscle did not affect cardiac output. These studies emphasize the importance for novel therapeutic approaches that target the vasculature in the treatment of insulin-resistant muscle.
Insights
Reduced vascular endothelial growth factor (VEGF) leads to fewer capillaries in muscles, causing insulin resistance. Targeting blood vessels may treat muscle insulin resistance.
Area of Science:
- Physiology
- Molecular Biology
- Endocrinology
Background:
- Muscle insulin resistance is linked to reduced vascular endothelial growth factor (VEGF) and capillary density.
- VEGF plays a crucial role in maintaining vascular health and function in muscle tissue.
Purpose of the Study:
- To investigate if reduced muscle capillary density, caused by VEGF deletion, contributes to muscle insulin resistance.
- To determine the role of VEGF in skeletal and cardiac muscle insulin sensitivity.
Main Methods:
- Generated mice with skeletal and cardiac muscle-specific VEGF deletion (mVEGF(-/-)).
- Compared capillary density, glucose metabolism, and insulin signaling in mVEGF(-/-) and wild-type littermates.
- Assessed insulin-stimulated glucose uptake and myocyte insulin action.
Main Results:
- mVEGF(-/-) mice exhibited significantly reduced capillary density in skeletal (~60%) and cardiac (~50%) muscle.
- Fasting glucose turnover was increased, and insulin-stimulated glucose disappearance was blunted in mVEGF(-/-) mice.
- Impaired insulin-stimulated muscle glucose uptake was attributed to reduced muscle perfusion, not myocyte insulin resistance.
Conclusions:
- Muscle capillary rarefaction, driven by VEGF deficiency, critically contributes to muscle insulin resistance.
- These findings highlight the vasculature as a key target for treating insulin-resistant muscle conditions.
- Therapeutic strategies aimed at improving vascular function may be beneficial for muscle insulin resistance.
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