Monitoring Angiogenesis in Brain Using Steady-State Quantification of ΔR2 with MION Infusion

Abstract

An MRI method for quantification of cerebral blood volume (CBV) in time-course studies of angiogenesis is described. Angiogenesis was stimulated by acclimation to hypoxia. The change in relaxation rate, R2, which is relatively sensitive to the microvasculature, was quantified before and after infusion of a superparamagnetic vascular contrast agent (MION). The ΔR2 was measured in serum and brain parenchyma with a multiecho sequence. In vitro and in vivo calibration curves of MION concentration vs. R2 were approximated by a linear function. CBV was 3.14 ± 0.32% (mean ± SE, n = 13) and 6.42 ± 0.54% (n = 4) before and after acclimation. A second acclimated group was hemodiluted to control for polycythemia. CBV was not significantly different between hemodiluted and nonhemodiluted groups. In animals where NMR measurements were taken before and after acclimation, there was a 120% increase in CBV. The NMR technique was validated using quantitative morphometrics, which showed an increase of 147% in CBV with acclimation. We found a linear correlation between MRI and the morphometric results for CBV, as well as demonstrating a quantitative equivalence for relative changes in CBV. This article describes a simple, repeatable method of imaging brain microvascular volume using a plasma-based contrast agent that can be applied to longitudinal studies of angiogenesis. © 2003 Wiley-Liss, Inc.