Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.
Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.
Takeshita
S
S
Department of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135.
Zheng
L P
LP
Brogi
E
E
Kearney
M
M
Pu
L Q
LQ
Bunting
S
S
Ferrara
N
N
Symes
J F
JF
Isner
J M
JM
D000792:Angiography; D000818:Animals; D016466:CHO Cells; D002196:Capillaries / Q000187:drug effects; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000096:biosynthesis / Q000627:therapeutic use*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007269:Injections, Intra-Arterial; D007511:Ischemia / Q000628:therapy*; D008222:Lymphokines / Q000008:administration & dosage / Q000096:biosynthesis / Q000627:therapeutic use*; D008297:Male; D009132:Muscles / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000627:therapeutic use; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors