Muscle-specific VEGF deficiency greatly reduces exercise endurance in mice.
Vascular endothelial growth factor (VEGF) is required for vasculogenesis and angiogenesis during embryonic and early postnatal life. However the organ-specific functional role of VEGF in adult life, particularly in skeletal muscle, is less clear. To explore this issue, we engineered skeletal muscle-targeted VEGF deficient mice (mVEGF-/-) by crossbreeding mice that selectively express Cre recombinase in skeletal muscle under the control of the muscle creatine kinase promoter (MCKcre mice) with mice having a floxed VEGF gene (VEGFLoxP mice). We hypothesized that VEGF is necessary for regulating both cardiac and skeletal muscle capillarity, and that a reduced number of VEGF-dependent muscle capillaries would limit aerobic exercise capacity. In adult mVEGF-/- mice, VEGF protein levels were reduced by 90 and 80% in skeletal muscle (gastrocnemius) and cardiac muscle, respectively, compared to control mice (P < 0.01). This was accompanied by a 48% (P < 0.05) and 39% (P < 0.05) decreases in the capillary-to-fibre ratio and capillary density, respectively, in the gastrocnemius and a 61% decrease in cardiac muscle capillary density (P < 0.05). Hindlimb muscle oxidative (citrate synthase, 21%; beta-HAD, 32%) and glycolytic (PFK, 18%) regulatory enzymes were also increased in mVEGF-/- mice. However, this limited adaptation to reduced muscle VEGF was insufficient to maintain aerobic exercise capacity, and maximal running speed and endurance running capacity were reduced by 34% and 81%, respectively, in mVEGF-/- mice compared to control mice (P < 0.05). Moreover, basal and dobutamine-stimulated cardiac function, measured by transthoracic echocardiography and left ventricular micromanomtery, showed only a minimal reduction of contractility (peak +dP/dt) and relaxation (peak -dP/dt, tau(E)). Collectively these data suggests adequate locomotor muscle capillary number is important for achieving full exercise capacity. Furthermore, VEGF is essential in regulating postnatal muscle capillarity, and that adult mice, deficient in cardiac and skeletal muscle VEGF, exhibit a major intolerance to aerobic exercise.
Olfert
I Mark
IM
Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0623, USA. molfert@ucsd.edu
Howlett
Richard A
RA
Tang
Kechun
K
Dalton
Nancy D
ND
Gu
Yusu
Y
Peterson
Kirk L
KL
Wagner
Peter D
PD
Breen
Ellen C
EC
D000818:Animals; D002196:Capillaries / Q000254:growth & development / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology; D004452:Echocardiography; D005838:Genotype; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D006651:Histocytochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000166:cytology / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D010101:Oxygen Consumption / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency* / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology
D006454:Hemoglobins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2