Bevacizumab Attenuates VEGF-Induced Angiogenesis and Vascular Malformations in the Adult Mouse Brain

Center for Cerebrovascular Research, University of California, San Francisco, Department of Anesthesia and Perioperative Care, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110, USA.
Stroke (Impact Factor: 5.72). 05/2012; 43(7):1925-30. DOI: 10.1161/STROKEAHA.111.647982
Source: PubMed


Vascular endothelial growth factor (VEGF) expression is elevated in human brain arteriovenous malformations (bAVM). We have developed a bAVM model in the adult mouse by focal Alk1 gene deletion and human VEGF stimulation. We hypothesized that once the abnormal vasculature has been established, tonic VEGF stimulation is necessary to maintain the abnormal phenotype, and VEGF antagonism by bevacizumab (Avastin) would reduce vessel density and attenuate the dysplastic vascular phenotype.
Angiogenesis and bAVM were induced by injection of adeno-associated viral vector expressing human VEGF alone into the brain of wild-type mice or with adenoviral vector expressing Cre recombinase (Ad-Cre) into Alk1(2f/2f) mice. Six weeks later, bevacizumab or trastuzumab (Herceptin, bevacizumab control) was administered. Vessel density, dysplasia index, vascular cell proliferation and apoptosis, and human IgG were assessed (n=6/group).
Compared with trastuzumab (15 mg/kg), administration of 5, 10, and 15 mg/kg of bevacizumab to adeno-associated viral vector expressing human VEGF treated wild-type mice reduced focal vessel density (P<0.05); administration of 5 mg/kg bevacizumab decreased proliferating vascular cells (P=0.04) and increased TUNEL-positive vascular cells (P=0.03). More importantly, bevacizumab (5 mg/kg) treatment reduced both vessel density (P=0.01) and dysplasia index (P=0.02) in our bAVM model. Human IgG was detected in the vessel wall and in the parenchyma in the angiogenic foci of bevacizumab-treated mice.
We provide proof-of-principle that, once abnormal AVM vessels have formed, VEGF antagonism may reduce the number of dysplastic vessels and should be evaluated further as a therapeutic strategy for the human disease.

15 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: We investigated the effects of bevacizumab and rapamycin on central corneal opacity and apoptotic keratocyte number after photorefractive keratectomy (PRK) followed by ultraviolet B (UV-B) irradiation. Methods: A total of 60 right eyes of Sprague-Dawley rats in four groups (n = 15 each) underwent PRK ablation to 80 μm with a 3-mm zone. Sponges soaked with 0.02% mitomycin C (MMC), 2.5% bevacizumab, 0.01% rapamycin, and balanced saline solution were applied for 2 minutes to these eyes in the MMC, bevacizumab, rapamycin, and control groups, respectively. At 3 weeks after PRK, all right eyes were exposed to 100 mJ/cm(2) UV-B irradiation. Biomicroscopy was used to determine the amount of haze, and TUNEL staining for apoptosis and histology were performed at 3, 6, and 12 weeks. Results: Contrary to the results at 3 weeks, central corneal haze, and apoptotic keratocyte and keratocyte number decreased significantly in the MMC, bevacizumab, and rapamycin groups compared to the control group, and the keratocyte number was lower in the MMC group than the bevacizumab and rapamycin groups at 6 weeks (all P < 0.05). At 12 weeks, the apoptotic keratocyte number was lower in the MMC, bevacizumab, and rapamycin groups than the control group, and the keratocyte number was significantly lower in the MMC than the rapamycin and control groups (all P < 0.05). Conclusions: Intraoperative bevacizumab and rapamycin administration decreases central corneal haze and apoptotic keratocyte number after PRK. Bevacizumab and rapamycin may be safe alternatives to MMC during refractive surgery to prevent postoperative corneal opacity less affecting the keratocyte number.
    Investigative ophthalmology & visual science 10/2012; 53(12). DOI:10.1167/iovs.12-10494 · 3.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral Arteriovenous Malformations (AVM) occurs universally in 1.1 per 100000 people. They are the cause of serious neurological morbidity or even death when they bleed. AVM’s are not necessarily static congenital abnormalities. They can undergo internal changes due to angiogenesis resulting in vascular remodelling. They can even re-grow after successful therapy. Vascular endothelial growth factors (VEGF) play an important role in angiogenesis. Drugs are available that block the action of VEGF on VEGFR receptors on the endothelial cell surface. This blockade causes an anti-angiogenetic effect. Anti-angiogenic drugs are widely used as adjuvant therapy in the management of cancers because they suppress the formation of new blood vessels required by the tumour for growth. For similar reasons they are used in the treatment of age related macular degeneration.The present treatment options for AVM’s are surgery, embolization and irradiation either on their own or in combination. Irradiation with Stereotactic Radiosurgery (SRS) offers the advantage of being non invasive, but relies on the late radiation effects to achieve its therapeutic goal of complete obliteration. This latent time (1 – 3 years) during which the risk for a bleed remains is an inherent drawback of SRS. The histopathology of surgical specimens of post SRS AVM’s demonstrates a role of endothelial cells in repairing the radiation damage. Suppressing their activity post SRS by a VEGF Blockade has the potential to enhance the radiation damage and hence speed up the obliteration process and reduce the latent time. It is postulated that such a “VEGF Blockade” could be useful as an adjuvant therapy to SRS. In addition there is also the potential for a neo adjuvant use, whereby a VEGF blockade could cause regression in the size of the AVM, making definite therapy easier. The rationale for the VEGF-blockade concept will be presented and discussed.
    Iranian Journal of Medical Hypotheses and Ideas 01/2013; 8(2). DOI:10.1016/j.jmhi.2013.10.001
  • [Show abstract] [Hide abstract]
    ABSTRACT: This manuscript provides an updated review of clinical and scientific or genetic updates in vascular anomalies, with an emphasis on essential information for the interventional radiologist. Citations include concise reviews and reliable websites which provide supplementary background. This manuscript elucidates the following: (1) not every vascular lesion is a hemangioma, (2) the Kasabach-Merritt phenomenon is not seen in association with typical hemangiomas, (3) many new basic research and genetic findings in vascular anomalies may influence the clinical evaluation and diagnosis (as well as provide rationale for future targeted therapies which may successfully ameliorate or eradicate these conditions), (4) it is essential to communicate with the clinician and patient to understand the history, physical findings, and best approach to evaluation and management, and (5) multiple specialists are often involved, and multidisciplinary teams of physicians and ancillary healthcare workers often collaborate.
    Techniques in vascular and interventional radiology 03/2013; 16(1):2-11. DOI:10.1053/j.tvir.2013.01.002
Show more