Inhibition of vascular endothelial growth factor-mediated neointima progression with angiostatin or paclitaxel.
OBJECTIVE
Therapeutic angiogenesis represents a new paradigm for treatment of ischemic vascular syndromes. However, vascular endothelial growth factor (VEGF) enhances the rate and degree of plaque formation. This study evaluates the potential to block these effects nonspecifically with paclitaxel or specifically with angiostatin.


METHODS
Recombinant human VEGF(165) (rhVEGF) was administrated intramuscularly (2-microg/kg single injection) in combination with adventitial delivery of paclitaxel, angiostatin, or vehicle alone at the site of femoral arterial balloon overdilation injury in New Zealand White rabbits (n = 5 per treatment). Five additional animals with no rhVEGF and no adventitial delivery served as procedural controls. All rabbits were fed according to a 0.25% cholesterol diet beginning 28 days before angioplasty. Treated arteries were harvested after 7 days and evaluated to determine intima-to-media (I/M) ratios, macrophage infiltrate, and endothelial cell density.


RESULTS
On histologic analysis, the rhVEGF/gel control group exhibited a mean I/M ratio of 0.337 +/- 0.028, a 77% increase over procedural controls, which exhibited a mean I/M of 0.190 +/- 0.010. rhVEGF/paclitaxel reduced I/M ratios to 0.151 +/- 0.007. In contrast, specific antiangiogenic therapy (rhVEGF/angiostatin) reduced I/M ratios to 0.032 +/- 0.003, a 91% decrease relative to rhVEGF/gel and an 83% decrease relative to procedural controls (P =.001 for each comparison). Local macrophages and endothelial cells also decreased with treatment.


CONCLUSIONS
This study shows that paclitaxel and angiostatin each afford local protection against rhVEGF-mediated increases in neointima. Angiostatin further prevents progression of underlying neointima. These local therapies may allow broader use of therapeutic angiogenesis while avoiding and treating potentially undesirable effects.
Celletti
Francesca L
FL
Department of Cardiovascular and Interventional Radiology, Room H 3647, Stanford University Medical Center, Stanford, California 94305, USA.
Waugh
Jacob M
JM
Amabile
Philippe G
PG
Kao
Ed Y
EY
Boroumand
Sara
S
Dake
Michael D
MD
D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000139:chemically induced / Q000517:prevention & control*; D016228:Endothelial Growth Factors / Q000008:administration & dosage*; D005263:Femoral Artery; D007124:Immunoenzyme Techniques; D007273:Injections, Intramuscular; D007511:Ischemia; D008222:Lymphokines / Q000008:administration & dosage*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010958:Plasminogen / Q000494:pharmacology*; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D043168:Angiostatins; D010958:Plasminogen; D017239:Paclitaxel