To determine the involvement of vascular endothelial growth factor (VEGF) and its receptors Flk-1 and Flt-1 in capillary growth in ischaemic skeletal muscle, extensor digitorum longus muscles from hindlimbs of Sprague—Dawley rats were studied at 1, 2 and 5 week intervals after iliac artery ligation. Muscle VEGF protein levels (as determined by Western-blot analysis) increased only after 2 (60%) and 5 (80%) weeks, with more capillaries positively immunostained for VEGF than in control muscles. Ischaemia-induced angiogenesis was gradual, with capillary proliferation at 1 and 2 weeks and capillary:fibre ratio increased 20% after 5 weeks. This was associated with an initial doubling of Flk-1 protein after 1 week that declined below control levels by 5 weeks, whereas Flt-1 expression was elevated more than 40% at all time points. During more sustained ischaemia (femoral ligation 3 weeks after iliac ligation), VEGF protein level at 5 weeks was even higher, but Flt-1 and Flk-1 were unchanged from control levels and no capillary growth occurred. Intermittent electrical stimulation (10 Hz, 7×15 min/day) of these ischaemic muscles between weeks 3–5 did not elevate VEGF further, but increased Flk-1 by 32%, decreased Flt-1 by 71%, and led to significant capillary growth. These results demonstrate that during chronic muscle ischaemia Flk-1 and Flt-1 are regulated differentially and that electrical stimulation of ischaemic muscles can promote angiogenesis via Flk-1 up-regulation. Even when ischaemic muscle VEGF levels are high, capillary growth appears to be dependent on the presence of Flk-1.
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Research Article|
October 01 2003
Differential expression of Flk-1 and Flt-1 in rat skeletal muscle in response to chronic ischaemia: favourable effect of muscle activity
Malgorzata MILKIEWICZ;
*School of Sport and Exercise Sciences, University of Birmingham, Birmingham B15 2TT, U.K.
†Department of Physiology, University of Birmingham, Birmingham B15 2TT, U.K.
Correspondence: Dr M. Milkiewicz, Department of Physiology, University of Birmingham, Birmingham B15 2TT, U.K. (e-mail [email protected]).
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Olga HUDLICKA;
Olga HUDLICKA
†Department of Physiology, University of Birmingham, Birmingham B15 2TT, U.K.
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Julie VERHAEG;
Julie VERHAEG
*School of Sport and Exercise Sciences, University of Birmingham, Birmingham B15 2TT, U.K.
†Department of Physiology, University of Birmingham, Birmingham B15 2TT, U.K.
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Stuart EGGINTON;
Stuart EGGINTON
†Department of Physiology, University of Birmingham, Birmingham B15 2TT, U.K.
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Margaret D. BROWN
Margaret D. BROWN
*School of Sport and Exercise Sciences, University of Birmingham, Birmingham B15 2TT, U.K.
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Publisher: Portland Press Ltd
Received:
January 27 2003
Revision Received:
May 12 2003
Accepted:
June 02 2003
Accepted Manuscript online:
June 02 2003
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2003 The Biochemical Society
2003
Clin Sci (Lond) (2003) 105 (4): 473–482.
Article history
Received:
January 27 2003
Revision Received:
May 12 2003
Accepted:
June 02 2003
Accepted Manuscript online:
June 02 2003
Citation
Malgorzata MILKIEWICZ, Olga HUDLICKA, Julie VERHAEG, Stuart EGGINTON, Margaret D. BROWN; Differential expression of Flk-1 and Flt-1 in rat skeletal muscle in response to chronic ischaemia: favourable effect of muscle activity. Clin Sci (Lond) 1 October 2003; 105 (4): 473–482. doi: https://doi.org/10.1042/CS20030035
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