Dataset Information

Monitoring vascular permeability and remodeling after endothelial injury in a murine model using a magnetic resonance albumin-binding contrast agent.

ABSTRACT:

Background

Despite the beneficial effects of vascular interventions, these procedures may damage the endothelium leading to increased vascular permeability and remodeling. Re-endothelialization of the vessel wall, with functionally and structurally intact cells, is controlled by endothelial nitric oxide synthase (NOS3) and is crucial for attenuating adverse effects after injury. We investigated the applicability of the albumin-binding MR contrast agent, gadofosveset, to noninvasively monitor focal changes in vascular permeability and remodeling, after injury, in NOS3-knockout (NOS3(-/-)) and wild-type (WT) mice in vivo.

Methods and results

WT and NOS3(-/-) mice were imaged at 7, 15, and 30 days after aortic denudation or sham-surgery. T1 mapping (R1=1/T1, s(-1)) and delayed-enhanced MRI were used as measurements of vascular permeability (R1) and remodeling (vessel wall enhancement, mm(2)) after gadofosveset injection, respectively. Denudation resulted in higher vascular permeability and vessel wall enhancement 7 days after injury in both strains compared with sham-operated animals. However, impaired re-endothelialization and increased neovascularization in NOS3(-/-) mice resulted in significantly higher R1 at 15 and 30 days post injury compared with WT mice that showed re-endothelialization and lack of neovascularization (R1 [s(-1)]=15 days: NOS3 (-/-)4.02 [interquartile range, IQR, 3.77-4.41] versus WT2.39 [IQR, 2.35-2.92]; 30 days: NOS3 (-/-)4.23 [IQR, 3.94-4.68] versus WT2.64 [IQR, 2.33-2.80]). Similarly, vessel wall enhancement was higher in NOS3(-/-) but recovered in WT mice (area [mm(2)]=15 days: NOS3 (-/-)5.20 [IQR, 4.68-6.80] versus WT2.13 [IQR, 0.97-3.31]; 30 days: NOS3 (-/-)7.35 [IQR, 5.66-8.61] versus WT1.60 [IQR, 1.40-3.18]). Ex vivo histological studies corroborated the MRI findings.

Conclusions

We demonstrate that increased vascular permeability and remodeling, after injury, can be assessed noninvasively using an albumin-binding MR contrast agent and may be used as surrogate markers for evaluating the healing response of the vessel wall after injury.

SUBMITTER: Lavin B

PROVIDER: S-EPMC4405074 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

Monitoring vascular permeability and remodeling after endothelial injury in a murine model using a magnetic resonance albumin-binding contrast agent.

Lavin Begoña B Phinikaridou Alkystis A Lorrio Silvia S Zaragoza Carlos C Botnar René M RM Botnar René M RM

Circulation. Cardiovascular imaging 20150401 4

<h4>Background</h4>Despite the beneficial effects of vascular interventions, these procedures may damage the endothelium leading to increased vascular permeability and remodeling. Re-endothelialization of the vessel wall, with functionally and structurally intact cells, is controlled by endothelial nitric oxide synthase (NOS3) and is crucial for attenuating adverse effects after injury. We investigated the applicability of the albumin-binding MR contrast agent, gadofosveset, to noninvasively mon ...[more]

PMID: 25873720

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Project description:BACKGROUND:Compromised structural integrity of the endothelium and higher microvessel density increase vascular permeability. We investigated whether vascular permeability measured in vivo by magnetic resonance imaging using the albumin-binding contrast agent, gadofosveset, is a surrogate marker of rupture-prone atherosclerotic plaque in a rabbit model. METHODS AND RESULTS:New Zealand white rabbits (n=10) were rendered atherosclerotic by cholesterol-diet and endothelial denudation. Plaque rupture was triggered with Russell's viper venom and histamine. Animals were imaged pre-triggering, at 3 and 12 weeks, to quantify plaque area, vascular permeability, vasodilation, and stiffness and post-triggering to identify thrombus. Plaques identified on the pretrigger scans were classified as stable or rupture-prone based on the absence or presence of thrombus on the corresponding post-trigger magnetic resonance imaging, respectively. All rabbits had developed atherosclerosis, and 60% had ruptured plaques. Rupture-prone plaques had higher vessel wall relaxation rate (R1; 2.30±0.5 versus 1.86±0.3 s-1; P<0.001), measured 30 minutes after gadofosveset administration, and higher R1/plaque area ratio (0.70±0.06 versus 0.47±0.02, P= 0.01) compared with stable plaque at 12 weeks. Rupture-prone plaques had higher percent change in R1 between the 3 and 12 weeks compared with stable plaque (50.80±7.2% versus 14.22±2.2%; P<0.001). Immunohistochemistry revealed increased vessel wall albumin and microvessel density in diseased aortas and especially in ruptured plaque. Electron microscopy showed lack of structural integrity in both luminal and microvascular endothelium in diseased vessels. Functionally, the intrinsic vasodilation of the vessel wall decreased at 12 weeks compared with 3 weeks (18.60±1.0% versus 23.43±0.8%; P<0.001) and in rupture-prone compared with stable lesions (16.40±2.0% versus 21.63±1.2%; P<0.001). Arterial stiffness increased at 12 weeks compared with 3 weeks (5.00±0.1 versus 2.53±0.2 m/s; P<0.001) both in animals with stable and rupture-prone lesions. CONCLUSIONS:T1 mapping using an albumin-binding contrast agent (gadofosveset) could quantify the changes in vascular permeability associated with atherosclerosis progression and rupture-prone plaques.

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Dataset Information

Monitoring vascular permeability and remodeling after endothelial injury in a murine model using a magnetic resonance albumin-binding contrast agent.

Background

Methods and results

Conclusions

Publications

Monitoring vascular permeability and remodeling after endothelial injury in a murine model using a magnetic resonance albumin-binding contrast agent.

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