Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, and transgene expression from adenovirus vectors can provide in vivo delivery of proteins. On the basis of this knowledge, we hypothesized that local administration of a replication-deficient adenovirus vector expressing complementary DNA for VEGF (AdVEGF) would induce collateral vessel formation in the setting of ischemia that could protect against subsequent acute vascular occlusion.


METHODS
Hindlimb ischemia was induced in Sprague-Dawley rats by means of unilateral ligation of the common iliac artery immediately followed by administration of 4 x 10(9)-plaque-forming units VEGF, the control vector AdNull, or phosphate-buffered saline solution into the iliofemoral adipose tissue and thigh muscles. Untreated rats with common iliac ligation were used as an additional control group.


RESULTS
Local VEGF expression was observed for 5 days in AdVEGF-treated rats but not in controls. Three weeks after ligation and vector administration, the ipsilateral femoral artery was ligated for a model of an acute vascular occlusion in the setting of preexisting ischemia. Blood flow to the ischemic hindlimb relative to the contralateral hindlimb evaluated with color microspheres demonstrated significantly increased blood flow in the AdVEGF-treated rats compared with each control group (p < 0.0001). Relative blood flow assessed by means of 99mTc-sestamibi radionuclide scans also demonstrated increased blood flow to the ligated hindlimb of AdVEGF-treated rats compared with each control group (p < 0.002). AdVEGF-treated rats also demonstrated increased vascularity in the ligated limb compared with each control group as assessed by means of angiography (p < 0.0001) and histologic quantification of blood vessels less than 80 microm diameter in local adipose tissue and capillaries per muscle fiber (p < 0.0002). AdVEGF treatment prevented a rise in femoral venous lactate femoral venous concentrations 1 hour after femoral artery ligation in control rats (p < 0.04).


CONCLUSIONS
An adenovirus vector expressing VEGF complementary DNA is capable of stimulating an angiogenic response that protects against acute vascular occlusion in the setting of preexisting ischemia, suggesting that in vivo gene transfer of VEGF complementary DNA might be useful in prophylaxis of advancing arterial occlusive disease.
Mack
C A
CA
Department of Cardiothoracic Surgery, The New York Hospital-Cornell Medical Center, NY 10021, USA.
Magovern
C J
CJ
Budenbender
K T
KT
Patel
S R
SR
Schwarz
E A
EA
Zanzonico
P
P
Ferris
B
B
Sanborn
T
T
Isom
P
P
Ferris
B
B
Sanborn
T
T
Isom
O W
OW
Crystal
R G
RG
Rosengart
T K
TK
D000256:Adenoviridae / Q000235:genetics*; D000273:Adipose Tissue / Q000098:blood supply; D000792:Angiography; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control; D002196:Capillaries / Q000000981:diagnostic imaging; D003097:Collateral Circulation / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use; D005263:Femoral Artery / Q000601:surgery; D005268:Femoral Vein; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006614:Hindlimb / Q000098:blood supply*; D007083:Iliac Artery / Q000601:surgery; D007273:Injections, Intramuscular; D007511:Ischemia / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D007773:Lactates / Q000097:blood; D008026:Ligation; D008222:Lymphokines / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use; D008297:Male; D008863:Microspheres; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D017256:Technetium Tc 99m Sestamibi; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D007773:Lactates; D008222:Lymphokines; D019275:Radiopharmaceuticals; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017256:Technetium Tc 99m Sestamibi