VEGF-A splice variants and related receptor expression in human skeletal muscle following submaximal exercise.
VEGF-A contributes to muscle tissue angiogenesis following aerobic exercise training. The temporal response of the VEGF-A isoforms and their target receptors has not been comprehensively profiled in human skeletal muscle. We combined submaximal exercise with and without reduced leg blood flow to establish whether ischemia-induced metabolic stress was an important physiological stimuli responsible for regulating the VEGF-A system in humans. Nine healthy men performed two 45-min bouts of one-leg knee-extension exercise, with and without blood flow restriction. Muscle biopsies were obtained at rest and 2 and 6 h after exercise. Expression (mRNA) of the VEGF-A splice variants and related receptors [VEGF receptor (VEGFR)-1, VEGFR-2, and neuropilin-1] was determined by using qPCR. VEGF-A(total) expression increased more robustly after exercise with reduced blood flow, and initially this principally reflected an increase in VEGF-A(165). Six hours after exercise, there was a relatively greater increase in VEGF-A(189), and this response was not influenced by blood flow conditions. VEGFR-1 mRNA expression increased 2 h after exercise, and neuropilin-1 expression was transiently reduced, while all three receptors increased by 6 h. There was no evidence for the expression of the inhibitory VEGF-A(165B) variant in human skeletal muscle. Our study, reflecting both VEGF-A ligand and receptors, implicates metabolic perturbation as a regulator of human muscle angiogenesis and demonstrates that VEGF-A splice variants are distinctly regulated. Our findings also indicate that all three receptor genes exhibit different pretranslational regulation, in response to exercise in humans.
Gustafsson
T
T
Karolinska Institute, Berzelius Väg 35, Stockholm 171 77, Sweden.
Ameln
H
H
Fischer
H
H
Sundberg
C J
CJ
Timmons
J A
JA
Jansson
E
E
D000222:Adaptation, Physiological / Q000235:genetics; D000293:Adolescent; D000328:Adult; D001783:Blood Flow Velocity / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics; D005080:Exercise Test; D005786:Gene Expression Regulation / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000235:genetics; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism*; D005082:Physical Exertion; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics* / Q000378:metabolism*; D015427:Reperfusion Injury / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*
D004274:DNA, Recombinant; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor