Abstract
Purpose: Subsurface blood vessels in the cerebral cortex have been identified as a bottleneck in cerebral perfusion with the potential for collateral remodeling. However, valid techniques for non-invasive, longitudinal characterization of neocortical microvessels are still lacking. In this study, we validated contrast-enhanced magnetic resonance imaging (CE-MRI) for in vivo characterization of vascular changes in a model of spontaneous collateral outgrowth following chronic cerebral hypoperfusion.Methods: C57BL/6J mice were randomly assigned to unilateral internal carotid artery occlusion or sham surgery and after 21 days, CE-MRI based on T2*-weighted imaging was performed using ultra-small superparamagnetic iron oxide nanoparticles to obtain subtraction angiographies and steady-state cerebral blood volume (ss-CBV) maps. First pass dynamic susceptibility contrast MRI (DSC-MRI) was performed for internal validation of ss-CBV. Further validation at the histological level was provided by ex vivo serial two-photon tomography (STP).Results: Qualitatively, an increase in vessel density was observed on CE-MRI subtraction angiographies following occlusion; however, a quantitative vessel tracing analysis was prone to errors in our model. Measurements of ss-CBV reliably identified an increase in cortical vasculature, validated by DSC-MRI and STP.Conclusion: Iron oxide nanoparticle-based ss-CBV serves as a robust, non-invasive imaging surrogate marker for neocortical vessels, with the potential to reduce and refine preclinical models targeting the development and outgrowth of cerebral collateralization.
Highlights
Cerebral collateral remodeling represents an endogenous rescue mechanism to cope with chronic cerebral hypoperfusion and determines the severity and outcome of hemodynamic stroke (Brozici et al, 2003; Todo et al, 2008; Menon et al, 2013; Lima et al, 2014)
We explored whether steady state cerebral blood volume (ss-cerebral blood vessel volume (CBV)) maps could serve as a surrogate marker for parenchymal blood vessel imaging (Figure 2A) and found a significant increase of ss-CBV in the right neocortex following internal carotid artery occlusion (ICAO) (Sham: 2.9 ± 0.3%; ICAO: 3.4 ± 0.4%; p = 0.04; n = 7 per group; Figure 2B)
In agreement with our parenchymal ss-CBV analysis but at clearly lower spatial resolution (Figure 3B), a significant increase in Dynamic susceptibility contrast (DSC)-rCBV following ICAO was noted for the right neocortex (Sham: 1.13 ± 0.02 AU; ICAO: 1.24 ± 0.02 AU; p = 0.000002; n = 7 per group; Figure 3C)
Summary
Cerebral collateral remodeling (cerebral arteriogenesis) represents an endogenous rescue mechanism to cope with chronic cerebral hypoperfusion and determines the severity and outcome of hemodynamic stroke (Brozici et al, 2003; Todo et al, 2008; Menon et al, 2013; Lima et al, 2014). Contrast enhanced magnetic resonance angiography (CE-MRA) was shown to allow direct detection of small-caliber parenchymal blood vessels in the mouse cerebral cortex using a semi-automated vessel tracing algorithm that permits diameter quantification among blood vessels enhanced at steady-state (Klohs et al, 2012). These findings are highly relevant, because non-invasive, longitudinal characterization of the cerebral vasculature has immediate implications for reduction and refinement of animal experiments next to understanding the etiology and course of neurovascular and neurodegenerative diseases. The aim of the present study was to validate iron oxide nanoparticlebased CE-MRI for blood vessel quantification in a preclinical mouse model of chronic cerebral hypoperfusion and spontaneous collateral remodeling by testing a previously reported vessel tracing algorithm and analyzing steady state blood volume maps (ss-CBV) against serial two-photon (STP) tomography
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