Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration.
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-1alpha 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.
Rissanen
Tuomas T
TT
Department of Molecular Medicine andthe National Bio-NMR Facility, A. I. Virtanen Institute, Kuopio University, Finland.
Vajanto
Ismo
I
Hiltunen
Mikko O
MO
Rutanen
Juha
J
Kettunen
Mikko I
MI
Niemi
Mari
M
Leppänen
Pia
P
Turunen
Mikko P
MP
Markkanen
Johanna E
JE
Arve
Katja
K
Alhava
Esko
E
Kauppinen
Risto A
RA
Ylä-Herttuala
Seppo
S
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002908:Chronic Disease; D016228:Endothelial Growth Factors / Q000378:metabolism* / Q000502:physiology; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D008222:Lymphokines / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D017978:Receptors, Growth Factor / Q000378:metabolism* / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D012038:Regeneration / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor