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¶
From the Department of Molecular Medicine* andthe National Bio-NMR Facility, A. I. Virtanen Institute, and the Departments ofSurgery andMedicine,¶ Kuopio University, and the Gene TherapyUnit, Kuopio University Hospital,Kuopio, Finland
Vascular endothelial growth factor (VEGF) is a hypoxia-inducible
endothelial cell mitogen and survival factor. Its receptor VEGFR-2
(KDR/Flk-1) mediates these effects. We studied the expression of VEGF
and VEGFR-2 in ischemic human and rabbit skeletal muscle by
immunohistochemistry and in situ hybridization. Human
samples were obtained from eight lower limb amputations because of
acute or chronic critical ischemia. In chronically ischemic human
skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic
and regenerating skeletal myocytes, whereas in acutely ischemic
limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle.
Hypoxia-inducible factor-1
was associated with VEGF and VEGFR-2
expression both in acute and chronic ischemia but not in regeneration.
Hindlimb ischemia was induced in 20 New Zealand White rabbits by
excising the femoral artery. Magnetic resonance imaging and
histological sections revealed extensive ischemic damage in the thigh
and leg muscles of ischemic rabbit hindlimbs with VEGF expression
similar to acute human lower limb ischemia. After 1 and 3 weeks of
ischemia VEGF expression was restricted to regenerating myotubes and by
6 weeks regeneration and expression of VEGF was diminished. VEGFR-2
expression was co-localized with VEGF expression in regenerating
myotubes. Macrophages and an increased number of capillaries were
associated with areas of ischemic muscle expressing VEGF and VEGFR-2.
In conclusion, two patterns of VEGF and VEGFR-2 expression in
human and rabbit ischemic skeletal muscle are demonstrated. In acute
skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in
the affected muscle. In chronic skeletal muscle ischemia and in
skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression
are restricted to atrophic and regenerating muscle cells suggesting the
operation of an autocrine pathway that may promote survival and
regeneration of myocytes.
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