Abstract 3194: Bevacizumab (Avastin) Crosses the Blood-brain Barrier and Attenuates VEGF-induced Angiogenesis and Vascular Dysplasia in an Adult Mouse Model of Brain Arteriovenous Malformations
Background and Purpose: The lesional phenotype of human brain arteriovenous malformation (bAVM) includes increased VEGF expression compared to normal brain. We developed an adult mouse model of bAVM by focal VEGF overexpression coupled with regional deletion of the Alk1 gene. Alk1 deletion alone was not sufficient to cause the bAVM phenotype, demonstrating VEGF plays a crucial role in bAVM pathogenesis. Bevacizumab (rhuMab VEGF; Avastin) is used to treat diseases characterized by pathologic angiogenesis. We hypothesized that bevacizumab would attenuate VEGF-induced brain angiogenesis and vascular dysplasia, once established, in the model.
Methods: Angiogenesis was induced in the brain of wild-type (WT) C57BL/6 mice by stereotactic injection of 2X109 genome copies (gcs) of adeno-associated viral vector expressing human VEGF (AAV-VEGF) into the basal ganglia. Six weeks later, bevacizumab (1, 5, 10, and 15 mg/kg) was administered intraperitoneally (IP) every other day for 10 days. Vessel density and Ki67-positive endothelial cell proliferation was quantified on sections of lectin-perfused brain (n=6/group). Bevacizumab (5 mg/kg) was administered for 10 days to our mouse bAVM model with AdCre (2X107 PFU) and AAV-VEGF (2X109 gcs) injected Alk1 floxed mice (loxP flanking exons 4-6) six weeks after vector injection. Trastuzumab (rhuMab HER2; Herceptin) was used as control treatment (n=7/group). Vessel density, dysplasia index (vessels >15 µm per 200 vessels), and anti-human IgG staining were assessed.
Results: All doses above 1 mg/kg of bevacizumab inhibited AAV-VEGF-induced brain angiogenesis in WT mice (p<0.05) as compared to trastuzumab (15 mg/kg) treated controls. Positive staining of anti-human IgG was detected in the brain parenchyma at the VEGF-induced angiogenic foci of mice treated with bevacizumab and trastuzumab. Bevacizumab (5 mg/kg) treatment decreased Ki67 positive endothelial cells (p=0.04) as compared to the trastuzumab treated controls. In our mouse model of bAVM, bevacizumab (5 mg/kg) treatment reduced both vessel density (p=0.01) and dysplasia index (p=0.02) as compared to trastuzumab treatment.
Conclusions: This is the first study to demonstrate penetration of bevacizumab and trastuzumab into VEGF-stimulated brain after IP injection, indicating that IP-delivered bevacizumab or trastuzumab can penetrate the blood-brain barrier in VEGF-stimulated WT brain regions. Bevacizumab led to a reduction of VEGF-induced brain angiogenesis and endothelial cellular proliferation in WT brain. Bevacizumab also reduced vessel density and cerebrovascular dysplasia in a model of bAVM. Further studies on the use of anti-angiogenic therapy in bAVM are warranted.
- © 2012 by American Heart Association, Inc.