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VEGF-A splice variants and related receptor expression in human skeletal muscle following submaximal exercise

¹Department of Physiology and Pharmacology, and ²Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska University Hospital, and ³Center for Genomics and Bioinformatics, Karolinska Institutet, Stockholm, Sweden

Submitted 21 December 2004 ; accepted in final form 15 January 2005

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-A₁₆₅. Six hours after exercise, there was a relatively greater increase in VEGF-A₁₈₉, 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.

vascular endothelial growth factor; angiogenesis; ischemia

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