Endothelial molecular changes in a rodent model of arteriovenous malformation

Karunanyaka, Athula; Tu, Jian; Watling, Amy; Storer, Kingsley P.; Windsor, Apsara; Stoodley, Marcus A.

doi:10.3171/jns.2008.109.12.1165

Cited by 22 publications

(30 citation statements)

References 34 publications

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“…However, this does not mean a 15-Gy dose of radiation is enough for vascular obliteration in AVMs. Clinical work has demonstrated that a margin dose of [16][17][18][19][20][21][22][23][24][25] Gy is necessary to achieve a satisfactory occlusion rate. 10,44 More work with smaller titrations of radiation doses and larger animal numbers per group is required to find the optimal radiation dose for vascular targeting.…”

Section: Discussionmentioning

confidence: 99%

“…25,33,38 A highly discriminating target, which dominantly expresses on AVM endothelium, is required for the success of this technique. We have investigated the molecular characteristics of the endothelial surface of AVM vessels 20,39,40 and, although differences were found in comparison with normal blood vessels, no target with adequate discriminating power has been found to date. However, radiation-induced molecular changes on the endothelial surface may be a promising source of targets for vascular targeting.…”

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confidence: 99%

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Live-cell imaging to detect phosphatidylserine externalization in brain endothelial cells exposed to ionizing radiation: implications for the treatment of brain arteriovenous malformations

Zhao

Johnson

Chen

et al. 2016

JNS

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Brain arteriovenous malformations (AVMs) are congenital abnormalities that consist of direct connections between arteries and veins, allowing highpressure arterial blood to flow into fragile cerebral veins, resulting in a high risk of hemorrhagic stroke. 16,37 The aim of AVM treatment is to prevent hemorrhage. 29 Treatment is effective only with complete AVM removal or obliteration. 14 Current treatments-namely surgery, endovascular occlusion, or stereotactic radiosurgery-are all associated with significant limitations.1,42 The surgical risk is generally unacceptable for lesions that are large, located in critical brain structures, or involve deep perforating arterabbreviatioNs AVM = arteriovenous malformation; FWD = forward; PI = propidium iodide; PS = phosphatidylserine; pSIVA = polarity-sensitive indicator of viability and apoptosis; SRS = stereotactic radiosurgery. obJective Stereotactic radiosurgery (SRS) is an established intervention for brain arteriovenous malformations (AVMs). The processes of AVM vessel occlusion after SRS are poorly understood. To improve SRS efficacy, it is important to understand the cellular response of blood vessels to radiation. The molecular changes on the surface of AVM endothelial cells after irradiation may also be used for vascular targeting. This study investigates radiation-induced externalization of phosphatidylserine (PS) on endothelial cells using live-cell imaging. methods An immortalized cell line generated from mouse brain endothelium, bEnd.3 cells, was cultured and irradiated at different radiation doses using a linear accelerator. PS externalization in the cells was subsequently visualized using polarity-sensitive indicator of viability and apoptosis (pSIVA)-IANBD, a polarity-sensitive probe. Live-cell imaging was used to monitor PS externalization in real time. The effects of radiation on the cell cycle of bEnd.3 cells were also examined by flow cytometry. results Ionizing radiation effects are dose dependent. Reduction in the cell proliferation rate was observed after exposure to 5 Gy radiation, whereas higher radiation doses (15 Gy and 25 Gy) totally inhibited proliferation. In comparison with cells treated with sham radiation, the irradiated cells showed distinct pseudopodial elongation with little or no spreading of the cell body. The percentages of pSIVA-positive cells were significantly higher (p = 0.04) 24 hours after treatment in the cultures that received 25- and 15-Gy doses of radiation. This effect was sustained until the end of the experiment (3 days). Radiation at 5 Gy did not induce significant PS externalization compared with the sham-radiation controls at any time points (p > 0.15). Flow cytometric analysis data indicate that irradiation induced growth arrest of bEnd.3 cells, with cells accumulating in the G2 phase of the cell cycle. coNclusioNs Ionizing radiation causes remarkable cellular changes in endothelial cells. Significant PS externalization is induced by radiation at doses of 15 Gy or higher, concomitant with a block in the cell cycle. Ra...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Live-cell imaging to detect phosphatidylserine externalization in brain endothelial cells exposed to ionizing radiation: implications for the treatment of brain arteriovenous malformations

Zhao

Johnson

Chen

et al. 2016

JNS

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“…It is possible that sufficient endothelial changes are caused by the shear stress from the high blood flow in these vessels 23 to enable the LPS/sTF treatment to induce thrombosis. Among rats in this group, thrombosis durability appeared less robust; rates of vessel occlusion at the later time points were lower.…”

Section: 15mentioning

confidence: 99%

“…23,31,33,49,55,56 The AVM model creation has been described in detail. 23,47,54,60 Briefly, rats were anesthetized, and an anterior cervical approach was used to expose the left common carotid artery and external jugular vein. Blood flow through the common carotid artery was measured by using a 1-mm Doppler ultrasonic probe (Transonic Systems Inc.).…”

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Durable thrombosis in a rat model of arteriovenous malformation treated with radiosurgery and vascular targeting

Reddy¹,

Duong

Fairhall

et al. 2014

JNS

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Object Radiosurgical treatment of brain arteriovenous malformations (AVMs) has the significant shortcomings of being limited to lesions smaller than 3 cm in diameter and of a latency-to-cure time of up to 3 years. A possible method of overcoming these limitations is stimulation of thrombosis by using vascular targeting. Using an animal model of AVM, the authors examined the durability of the thrombosis induced by the vascular-targeting agents lipopolysaccharide and soluble tissue factor conjugate (LPS/sTF). Methods Stereotactic radiosurgery or sham radiation was administered to 32 male Sprague-Dawley rats serving as an animal model of AVM; 24 hours after this intervention, the rats received an intravenous injection of LPS/sTF or normal saline. The animals were killed at 1, 7, 30, or 90 days after treatment. Immediately beforehand, angiography was performed, and model AVM tissue was harvested for histological analysis to assess rates of vessel thrombosis. Results Among rats that received radiosurgery and LPS/sTF, induced thrombosis occurred in 58% of small AVM vessels; among those that received radiosurgery and saline, thrombosis occurred in 12% of small AVM vessels (diameter < 200 μm); and among those that received LPS/sTF but no radiosurgery, thrombosis occurred at an intermediate rate of 43%. No systemic toxicity or intravascular thrombosis remote from the target region was detected in any of the animals. Conclusions Vascular targeting can increase intravascular thrombosis after radiosurgery, and the vessel occlusion is durable. Further work is needed to refine this approach to AVM treatment, which shows promise as a way to overcome the limitations of radiosurgery.

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“…We have developed an animal model that shares hemodynamic, structural, and molecular characteristics with human AVMs. 6,20 These characteristics make this model suitable for studying the early molecular responses of the AVM endothelial phenotype to radiation. However, before studying the molecular responses, one must understand the morphological, hemodynamic, and histological changes that occur after radiation treatment.…”

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Angiographic, hemodynamic, and histological changes in an animal model of brain arteriovenous malformations treated with Gamma Knife radiosurgery

Kashba

Patel

Grace

et al. 2015

JNS

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B rain arteriovenous malformations (AVMs) are a major cause of stroke in children and young adults. Surgical excision of an AVM offers immediate protection from hemorrhage and is suitable for small and superficial lesions. Approximately 70% of small AVMs (< 3 cm in diameter) are completely obliterated by 2-3 years after Gamma Knife surgery (GKS).1,3,23 However, patients treated with GKS remain at risk for suffering hemorrhage during the latent period before AVM occlusion. 9,15 A large number of patients who have large and/or deeply located AVMs cannot be treated using current methods.9 An improved method of treating AVMs is required for these patients.One potential new treatment is to induce thrombosis in abbreviatioNs AVM = arteriovenous malformation; GKS = Gamma Knife surgery; LCCA = left common carotid artery; LEJV = left external jugular vein; LINAC = linear accelerator. obJect Brain arteriovenous malformations (AVMs) are a major cause of stroke. Many AVMs are effectively obliterated by stereotactic radiosurgery, but such treatment for lesions larger than 3 cm is not as effective. Understanding the responses to radiosurgery may lead to new biological enhancements to this treatment modality. The aim of the present study was to investigate the hemodynamic, morphological, and histological effects of Gamma Knife surgery (GKS) in an animal model of brain AVM. methods An arteriovenous fistula was created by anastomosing the left external jugular vein to the side of the common carotid artery in 64 male Sprague-Dawley rats (weight 345 ± 8.8 g). Six weeks after AVM creation, 32 rats were treated with a single dose of GKS (20 Gy); 32 animals received sham radiation. Eight irradiated and 8 control animals were studied at each specified time point (1, 3, 6, and 12 weeks) for hemodynamic, morphological, and histological characterization. results Two AVMs showed partial angiographic obliteration at 6 weeks. Angiography revealed complete obliteration in 3 irradiated rats at 12 weeks. Blood flow in the ipsilateral proximal carotid artery (p < 0.001) and arterialized jugular vein (p < 0.05) was significantly lower in the irradiated group than in the control group. The arterialized vein's external diameter was significantly smaller in GKS-treated animals at 6 (p < 0.05) and 12 (p < 0.001) weeks. Histological changes included subendothelial cellular proliferation and luminal narrowing in GKS-treated animals. Neither luminal obliteration nor thrombus formation was identified at any of the time points in either irradiated or nonirradiated animals. coNclusioNs GKS produced morphological, angiographic, and histological changes in the model of AVM as early as 6 weeks after treatment. These results support the use of this model for studying methods to enhance radiation response in AVMs.

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Endothelial molecular changes in a rodent model of arteriovenous malformation

Abstract: The AVF model has a "nidus" with endothelial molecular changes similar to those observed in human AVMs, supporting its use as a model for studying the effects of radiosurgery on AVMs.

Cited by 22 publications

References 34 publications

Live-cell imaging to detect phosphatidylserine externalization in brain endothelial cells exposed to ionizing radiation: implications for the treatment of brain arteriovenous malformations

Live-cell imaging to detect phosphatidylserine externalization in brain endothelial cells exposed to ionizing radiation: implications for the treatment of brain arteriovenous malformations

Durable thrombosis in a rat model of arteriovenous malformation treated with radiosurgery and vascular targeting

Angiographic, hemodynamic, and histological changes in an animal model of brain arteriovenous malformations treated with Gamma Knife radiosurgery

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