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Inhibition of vascular endothelial growth factor-mediated neointima progression with angiostatin or paclitaxel
Francesca L Celletti1, Jacob M Waugh, Philippe G Amabile
1Department of Cardiovascular and Interventional Radiology, Room H 3647, Stanford University Medical Center, Stanford, California 94305, USA.
Purpose:
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.
Materials And 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.
Insights
Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) can cause plaque formation. Both paclitaxel and angiostatin blocked this effect, with angiostatin showing superior prevention of neointima progression.
Area of Science:
- Vascular biology
- Regenerative medicine
- Pharmacology
Background:
- Therapeutic angiogenesis aims to treat ischemic vascular syndromes.
- Vascular endothelial growth factor (VEGF) can paradoxically enhance plaque formation.
- Investigating methods to mitigate VEGF-induced neointima is crucial.
Purpose of the Study:
- To evaluate paclitaxel and angiostatin as potential blockers of VEGF-mediated plaque formation.
- To compare the efficacy of nonspecific (paclitaxel) and specific (angiostatin) blockade.
- To assess the impact on neointima, macrophage infiltration, and endothelial cell density.
Main Methods:
- New Zealand White rabbits underwent femoral arterial balloon overdilation injury.
- Recombinant human VEGF (rhVEGF) was administered with adventitial paclitaxel, angiostatin, or vehicle.
- Histologic analysis assessed intima-to-media ratios, macrophage infiltrate, and endothelial cell density.
Main Results:
- rhVEGF significantly increased intima-to-media ratios compared to controls.
- Paclitaxel reduced rhVEGF-induced increases in intima-to-media ratios.
- Angiostatin markedly reduced intima-to-media ratios, outperforming paclitaxel and controls.
Conclusions:
- Both paclitaxel and angiostatin provide local protection against rhVEGF-induced neointima.
- Angiostatin demonstrates superior efficacy in preventing neointima progression.
- These local therapies may enable safer application of therapeutic angiogenesis.