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.