Simulating vasogenic brain edema using chronic VEGF infusion

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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.

ABBREVIATIONS 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 = vascular endothelial growth factor.

Article Information

Correspondence Prashant Chittiboina, Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Diseases and Stroke, National Institutes of Health, 10 Center Dr., Rm. 3D20, Bethesda, MD 20892-1414. email: prashant.chittiboina@nih.gov.

INCLUDE WHEN CITING Published online January 6, 2017; DOI: 10.3171/2016.9.JNS1627.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Placement of the infusion cannula. Infusion cannulas were inserted stereotactically 1 mm anterior to the bregma and 2.5 mm lateral to the midline. The striatum was targeted for infusion. Edema was noted within striatum and the external capsule regions with VEGF infusions.

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    High-dose VEGF infusion causes IPHs. These axial T2-weighted MR images of animals receiving high-dose VEGF infusion (> 10 µg/ml) revealed severe edema extending along the external capsule (asterisk, A and B), and midline shift (B). A high incidence of IPH with local mass effect (arrowheads) in the juxtacanalicular region was also observed (C). The direction of cannula insertion is indicated by the arrow.

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    Preinfusion followed by VEGF infusion creates edema without confounding features of early surgical trauma. Representative coronal brain MR images of animals receiving control solution (A–C), a single 100-ng VEGF injection (D–F), 2 ng/hr of VEGF without preinfusion (G–I), and 2 ng/hr of VEGF following preinfusion with PBS (J–L). The upper row (A, D, G, and J) contains T2-weighted images, the middle row (B, E, H, and K) contains T1-weighted images, and the lower row (C, F, I, and L) contains T1-weighted postcontrast images. The injection or infusion site is marked by arrowheads. Neither the control infusion nor a single injection of VEGF resulted in edema (A and D) or BBB breakdown (C and F). Rats with no preinfusion demonstrated both edema (asterisks, G) and hemorrhage (arrowhead, H) and BBB breakdown (arrowhead, I). The presence of hemorrhage and surgical trauma significantly distorted normal brain structures. Preinfusion allowed for resolution of initial surgical trauma resulting in clearly demonstrated edema (asterisks, J) and BBB breakdown (arrowhead, L). All images were obtained at 144 hours.

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    Progression of edema formation on T2-weighted axial MRI. Sequential T2-weighted imaging of animals receiving control (A and B) infusion revealed a lack of edema formation at 12 hours (A) or 144 hours (B) near the cannula site (arrowheads). In animals receiving VEGF infusion, an early lack of edema (C) was followed by juxtacanalicular edema, and edema along the external capsule (asterisks) in late (i.e., 144 hours) images (D).

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    VEGF infusion results in increased volume and intensity of the T2-weighted signal. Three-dimensional segmentation analysis reveals a significantly increased region of T2 hyperintensity at 144 hours with VEGF infusion (A). Quantitative analysis of the T2 signal in the juxtacanalicular regions revealed a significant increase in the T2 signal due to VEGF infusion at 36 hours and beyond (B). Graphic demonstration of quantitative T2 mapping as a heat map reveals the extent of T2 hyperintensity. Early imaging at 12 hours with control (C) or VEGF (E) infusion and late (144-hour) imaging with control infusion (D) did not reveal an increased T2 signal. Edema within the striatum, white matter, and subcortical structures (F) with VEGF infusion at 144 hours is shown. *p < 0.05, ****p < 00001.

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    Volume of BBB breakdown is less than vasogenic edema. The volume of postcontrast T1 hyperintensity is significantly lower than the volume of T2 hyperintensity at 144 hours (A). Normalized T1 values in the juxtacanalicular region are elevated at 36 hours and beyond with VEGF infusion (B). Terminal Evans blue infusion (C) confirmed that the region of BBB breakdown was limited to the juxtacanalicular region in animals receiving VEGF (lower). Evans blue infusion (C) in animals receiving control solution (upper) did not reveal BBB breakdown. Note the expected coloration in choroid plexus bilaterally. Representative axial MR images from 1 animal demonstrate that the vasogenic edema (asterisks) on T2-weighted images extends beyond the juxtacanalicular regions (D–F). Postcontrast T1 enhancement (asterisks) in the same animal is limited to the juxtacanalicular region (G–I). ****p < 00001. Figure is available in color online only.

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    VEGF infusion causes interstitial edema without necrosis or inflammation. H & E preparations of the cannula site revealed significant local hypercellularity, inflammation, and edema with both control (A) and VEGF (B) infusions started immediately upon cannula insertion (cannula site denoted by asterisk). In animals that were preinfused with normal saline, edema and inflammation subsided in control animals (C). In animals infused with VEGF following priming (D), interstitial edema was noted, which was marked by a distinct lack of inflammatory infiltrate or necrosis. Bar = 100 μm. Figure is available in color online only.

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    VEGF infusion leads to vascular remodeling in the juxtacanalicular region. Increased intensity of CD105 signal (FITC) and laminin formation (Texas red) is demonstrated in addition to increased cellularity in the juxtacanalicular region with VEGF infusion (bottom row) when compared with control infusion (Control) or uninfused brain (Opp). Regions with vasogenic edema ipsilateral to VEGF infusion (Ipsi) did not demonstrate intense vascular remodeling. Bar = 100 μm.

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    VEGF leads to deranged neovascularization. Although AQP4 overexpression is noted in juxtacanalicular regions with VEGF infusion, inadequate coverage (arrowheads) of newly formed endothelial tubes (CD105 [FITC]) is observed (lower row). In uninfused brain (upper row), AQP4 tubes (Texas red) are closely aligned with endothelial tubes (CD105 [FITC]) demonstrated by colocalization on the merged image. Bar = 100 μm.

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    Chronic VEGF infusion does not lead to a reduction in claudin-5 expression in the juxtacanalicular region. Claudin-5 expression was not reduced in the juxtacanalicular region with VEGF infusion unlike as reported in previous studies with a single-dose VEGF injection. Robust cytoplasmic claudin expression was noted in regions of neovascularization. In uninfused brain (Opp), claudin-5 was localized to a membranous pattern as expected. Bar = 100 μm.

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