title: 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. jeffrey.s.bonner@vanderbilt.edu
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bonner
authors.forename: Louise
authors.initials: L
authors.lastname: Lantier
authors.forename: Clinton M
authors.initials: CM
authors.lastname: Hasenour
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism*; D017353:Gene Deletion; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse