Vascular endothelial cell growth factor and fibroblast growth factor 2 expression in patients with critical limb ischemia.
BACKGROUND
For patients with critical limb ischemia (CLI), there is a great need for alternative treatment strategies. One option is therapeutic angiogenesis by administration of vascular growth factors. The lack of convincing clinical data supporting this strategy may be due to the ignorance of endogenous angiogenic processes in CLI. To evaluate the importance of vascular growth factors in the pathogenesis in CLI and provide information for clinical growth factor treatment trials, we determined the levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) in the ischemic legs of patients with this disease.


METHODS
Skin and muscle biopsies from the calf and groin were gathered from 25 patients with CLI. Control samples came from 10 orthopedic patients and from 5 patients who were undergoing coronary artery bypass. The concentration of VEGF and FGF-2 in the biopsies was measured by enzyme-linked immunoassay, and to localize growth factor production, biopsied sections were immunostained.


RESULTS
Patients with CLI had lower levels of VEGF in distal skin samples than in proximal ones (mean difference: 16.7 pg/mg total protein, 95% confidence interval: -1.0 to -32.3, P =.038), but these levels were similar to those in distal samples from control subjects (8.0, -4.6 to 20.5, P =.65). In muscle, VEGF concentrations were similar in calf and groin (5.4, -12.4 to 23.1, P =.55), but distal levels were higher than in distal samples from control subjects (23.7, 1.2 to 56.7, P =.028). Skin FGF levels tended to be higher in distal samples (45.3, 26.5 to 117.5, P =.090) and were higher than in skin from control subjects (106.2, -11.4 to 223.8, P =.050). Also in muscle, distal samples had higher levels of FGF-2 (35.6, -1.6 to 59.7, P =.006), but these levels were similar to what was found in control subjects (29.4., -16.3 to 81.2, P =.39). Growth factors were located in connective tissue between muscle fibers. In skin, the predominant FGF-2 staining was just below the epidermal layer, whereas VEGF appeared in the dermal layer.


CONCLUSIONS
The results indicate that there are elevated concentrations of FGF-2 in calf muscle, whereas VEGF concentrations do not appear to be higher in the ischemic part of the leg in patients with CLI. These findings suggest that VEGF supplementation may be a more appropriate strategy for therapeutic angiogenesis to the calf area for CLI than FGF-2.
Department of Vascular Surgery, Karolinska Hospital, Stockholm, Sweden. ulrika.palmer.kazen@kirurgi.ki.se
Ulrika
U
Palmer-Kazen
David
D
Wariaro
Fuwen
F
Luo
Eric
E
Wahlberg
D000368:Aged; D000369:Aged, 80 and over; D001157:Arterial Occlusive Diseases / Q000150:complications / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D007511:Ischemia / Q000209:etiology / Q000378:metabolism*; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000737:chemistry; D012867:Skin / Q000098:blood supply* / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000096:biosynthesis*
D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2