title: Simulating vasogenic brain edema using chronic VEGF infusion.
abstract: OBJECTIVE To study peritumoral brain edema (PTBE), it is necessary to create a model that accurately simulates vasogenic brain edema (VBE) without introducing a complicated tumor environment. PTBE associated with brain tumors is predominantly a result of vascular endothelial growth factor (VEGF) secreted by brain tumors, and VEGF infusion alone can lead to histological blood-brain barrier (BBB) breakdown in the absence of tumor. VBE is intimately linked to BBB breakdown. The authors sought to establish a model for VBE with chronic infusion of VEGF that can be validated by serial in-vivo MRI and histological findings. METHODS Male Fischer rats (n = 182) underwent stereotactic striatal implantation of MRI-safe brain cannulas for chronic infusion of VEGF (2-20 µg/ml). Following a preinfusion phase (4-6 days), the rats were exposed to VEGF or control rat serum albumin (1.5 µl/hr) for as long as 144 hours. Serial MRI was performed during infusion on a high-field (9.4-T) machine at 12-24, 24-36, 48-72, and 120-144 hours. Rat brains were then collected and histological analysis was performed. RESULTS Control animals and animals infused with 2 µg/ml of VEGF experienced no neurological deficits, seizure activity, or abnormal behavior. Animals treated with VEGF demonstrated a significantly larger volume (42.90 ± 3.842 mm3) of T2 hyper-attenuation at 144 hours when compared with the volume (8.585 ± 1.664 mm3) in control animals (mean difference 34.31 ± 4.187 mm3, p < 0.0001, 95% CI 25.74-42.89 mm3). Postcontrast T1 enhancement in the juxtacanalicular region indicating BBB breakdown was observed in rats undergoing infusion with VEGF. At the later time periods (120-144 hrs) the volume of T1 enhancement (34.97 ± 8.99 mm3) was significantly less compared with the region of edema (p < 0.0001). Histologically, no evidence of necrosis or inflammation was observed with VEGF or control infusion. Immunohistochemical analysis demonstrated astrocyte activation, vascular remodeling, and increased claudin-5 expression in juxtacanalicular regions. Aquaporin-4 expression was increased in both control and VEGF animals in the juxtacanalicular regions. CONCLUSIONS The results of this study show that chronic brain infusion of VEGF creates a reliable model of VBE. This model lacks necrosis and inflammation that are characteristic of previous models of VBE. The model allows for a precise investigation into the mechanism of VBE formation. The authors also anticipate that this model will allow for investigation into the mechanism of glucocorticoid action in abrogating VBE, and to test novel therapeutic strategies targeting PTBE.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Piazza
authors.affiliation: NIH MRI Research Facility, NIH, Bethesda, Maryland.
authors.forename: Jeeva
authors.initials: J
authors.lastname: Munasinghe
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and.
authors.forename: Roger
authors.initials: R
authors.lastname: Murayi
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and.
authors.forename: Nancy
authors.initials: N
authors.lastname: Edwards
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and.
authors.forename: Blake
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and.
authors.forename: Stuart
authors.initials: S
authors.lastname: Walbridge
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and.
authors.forename: Marsha
authors.initials: M
authors.lastname: Merrill
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and.
authors.forename: Prashant
authors.initials: P
authors.lastname: Chittiboina
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000175:diagnosis / Q000209:etiology; D001932:Brain Neoplasms / Q000150:complications; D004195:Disease Models, Animal; D008279:Magnetic Resonance Imaging; D008297:Male; D011916:Rats, Inbred F344; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
chemical_list: D042461:Vascular Endothelial Growth Factor A
keywords: AQP4 = aquaporin-4; BBB = blood-brain barrier; CI = confidence interval; FITC = fluorescein isothiocyanate; FSE = fast spin-echo; GFAP = glial fibrillary acidic protein; IPH = intraparenchymal hemorrhage; PBS = phosphate-buffered saline; PTBE = peritumoral brain edema; ROI = region of interest; RSA = rat serum albumin; VBE = vasogenic brain edema; VEGF; VEGF = vascular endothelial growth factor; animal model; brain edema; cannula; infusion; peritumoral; rat; vasogenic