Muscle-Specific Vascular Endothelial Growth Factor Deletion Induces Muscle Capillary Rarefaction Creating Muscle Insulin Resistance

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.

Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

“…In the insulin-resistant states, VEGF actions in muscle vascular beds are impaired, which triggers muscle capillary regression (17,20). This is consistent with the observation that musclespecific VEGF deletion induces muscle capillary rarefaction and muscle insulin resistance (8,41).…”

Heat therapy promotes the expression of angiogenic regulators in human skeletal muscle

“…In the present study, an increase in VEGF mRNA expression in skeletal muscle was observed following both LBH and TH, demonstrating that this central proangiogenic factor might also mediate the angiogenic response to heat therapy in skeletal muscle. VEGF regulates basal and exercise training-induced increases in skeletal muscle capillarization (80), and muscle-specific deletion of this molecule leads to capillary rarefaction (3,52) and nearly abolishes exerciseinduced capillary growth (53).…”

Increased skeletal muscle capillarization enhances insulin sensitivity

“…Although defective glucose transport, mediated by GLUT4, is central to the development of skeletal muscle insulin resistance (40), it is recognized that diminished microvascular recruitment (8) and skeletal muscle rarefaction (5) are also important contributing factors.…”