Site-specific therapeutic angiogenesis after systemic administration of vascular endothelial growth factor.
OBJECTIVE
Recent experimental studies have established the feasibility of therapeutic angiogenesis; in all cases, this has been achieved with local administration of angiogenic growth factors. This study was designed to investigate the hypothesis that systemic administration of an angiogenic growth factor specifically mitogenic for endothelial cells--vascular endothelial growth factor (VEGF)--could augment collateral vessel development in a rabbit ischemic hindlimb model.


METHODS
Ten days after the ligation of the external iliac artery and excision of the common and superficial femoral arteries in one limb of New Zealand white rabbits, heparin (800 IU, n = 13), VEGF (1 mg, n = 3; 5 mg, n = 5), heparin (800 IU) + VEGF (1 mg, n = 5; 5 mg, n = 7), or saline solution (n = 8) was injected as a single bolus in a marginal ear vein. Collateral vessel formation and limb perfusion were assessed 10 and 30 days after treatment.


RESULTS
Animals in both VEGF-treated groups had a significantly higher (p < 0.01) increase in calf blood pressure ratio at day 10 (control, 0.44 +/- 0.02; heparin, 0.47 +/- 0.02; VEGF, 0.60 +/- 0.01; heparin+VEGF, 0.61 +/- 0.02) and day 30 (control, 0.49 +/- 0.05; heparin, 0.48 +/- 0.02; VEGF, 0.70 +/- 0.03; heparin+VEGF, 0.73 +/- 0.03). Both VEGF-treated groups had a significantly higher (p < 0.05) angiographic score at day 30 (control, 0.28 +/- 0.01; heparin, 0.28 +/- 0.01; VEGF, 0.37 +/- 0.01; heparin+VEGF, 0.38 +/- 0.02). Maximum flow reserve at day 30 in the ischemic limb was higher (p < 0.05) in VEGF-treated rabbits (control, 1.87 +/- 0.07; heparin, 1.92 +/- 0.08; VEGF, 2.42 +/- 0.16; heparin+VEGF, 2.33 +/- 0.12). Capillary density was higher (p < 0.01) in the ischemic muscles of VEGF-treated rabbits (control, 156 +/- 10/mm2; heparin, 178 +/- 8/mm2; VEGF, 230 +/- 10/mm2; heparin+VEGF, 233 +/- 8/mm2).


CONCLUSIONS
This series of in vivo experiments demonstrates that intravenous administration of VEGF, with or without heparin, results in both anatomic and physiologic evidence of enhanced collateral vessel formation in the rabbit ischemic hindlimb. Single-bolus systemic administration of VEGF may be a feasible therapeutic strategy in patients with lower-extremity ischemia.
Bauters
C
C
Department of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston.
Asahara
T
T
Zheng
L P
LP
Takeshita
S
S
Bunting
S
S
Ferrara
N
N
Symes
J F
JF
Isner
J M
JM
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D003097:Collateral Circulation / Q000187:drug effects / Q000502:physiology; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005240:Feasibility Studies; D005263:Femoral Artery / Q000473:pathology / Q000601:surgery; D006493:Heparin / Q000008:administration & dosage / Q000627:therapeutic use; D006614:Hindlimb / Q000098:blood supply; D007083:Iliac Artery / Q000473:pathology / Q000601:surgery; D007275:Injections, Intravenous; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011817:Rabbits; D012039:Regional Blood Flow / Q000502:physiology
D016228:Endothelial Growth Factors; D006493:Heparin