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Muscle‐specific VEGF deficiency greatly reduces exercise endurance in mice
Author(s) -
Olfert I. Mark,
Howlett Richard A.,
Tang Kechun,
Dalton Nancy D.,
Gu Yusu,
Peterson Kirk L.,
Wagner Peter D.,
Breen Ellen C.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2008.164384
Subject(s) - skeletal muscle , endocrinology , medicine , angiogenesis , citrate synthase , vascular endothelial growth factor , gastrocnemius muscle , cardiac muscle , cardiac function curve , biology , chemistry , heart failure , vegf receptors , biochemistry , enzyme
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 (MCK cre mice) with mice having a floxed VEGF gene (VEGF LoxP 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%; β‐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 +d P /d t ) and relaxation (peak –d P /d t , τ 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.