Magnetic resonance imaging of brain angiogenesis after stroke

Abstract

Stroke is a major cause of mortality and long-term disability worldwide. The initial changes in local perfusion and tissue status underlying loss of brain function are increasingly investigated with noninvasive imaging methods. In addition, there is a growing interest in imaging of processes that contribute to post-stroke recovery. In this review, we discuss the application of magnetic resonance imaging (MRI) to assess the formation of new vessels by angiogenesis, which is hypothesized to participate in brain plasticity and functional recovery after stroke. The excellent soft tissue contrast, high spatial and temporal resolution, and versatility render MRI particularly suitable to monitor the dynamic processes involved in vascular remodeling after stroke. Here we review recent advances in the field of MR imaging that are aimed at assessment of tissue perfusion and microvascular characteristics, including cerebral blood flow and volume, vascular density, size and integrity. The potential of MRI to noninvasively monitor the evolution of post-ischemic angiogenic processes is demonstrated from a variety of in vivo studies in experimental stroke models. Finally, we discuss some pitfalls and limitations that may critically affect the accuracy and interpretation of MRI-based measures of (neo)vascularization after stroke.

Fig. 1

Schematic representation of the cascade of events associated with angiogenesis after ischemic stroke. The physiological phenomena on the left side may be assessed with MRI (BBB blood–brain barrier, MVD microvessel density, CBV cerebral blood volume, CBF cerebral blood flow)

Fig. 2

Scanning electron micrographs of vascular casts of rat brains after unilateral occlusion of the middle cerebral artery (MCA). Three days after MCA occlusion, vascular budding was visible at many sites in the ipsilateral cortex, involving both small and large vessels (a white arrows). Microvessels formed connections with surrounding proliferating vessels (b, c white arrows). With time of survival, the conglomerates of microvessels increase in size, forming a dense and chaotic microvasculature surrounding larger microvessels (d). Inserted bars denote the magnification in each figure. Reproduced from Ref. [77] with permission from Lippincott, Williams and Wilkins

Fig. 3

Longitudinal changes in vascular density and CBF after 60 min of transient MCA occlusion in rats. Excised rat brains clearly show enhanced vascular density on the cortical surface of the ipsilateral hemisphere after MCA occlusion (a). Relative CBF maps (b) calculated from ASL experiments demonstrate a significantly increased CBF in the ipsilateral cortex from day 1 up to day 14 after MCA occlusion (c). Reproduced from Ref. [18] with permission from Lippincott Williams and Wilkins

Fig. 4

MRI and histology of a coronal rat brain slice at 7 days after 60-min unilateral MCA occlusion, resulting in a subcortical infarct. Pre-contrast R ₂ map displays the subcortical lesion with decreased R ₂ (a). The hyperintense spot inside the lesion on the pre-contrast R ₂ and R ₂^* maps reflects a bleeding (a and b). The enhanced R ₂^* in the ipsilateral hypothalamus may be a sign of increased venous blood volume (b). This area exhibited an increased ΔR ₂ value after administration of a superparamagnetic blood pool agent (USPIO), pointing toward an increase in the density of microvessels with a relatively small diameter (c). The high contrast-induced ΔR ₂^* in the entire lesion is reflective of increased total blood volume (d). The high ΔR ₂^*/ΔR ₂ ratio in the lesion is indicative of a relatively large vessel diameter (e), as was confirmed by histology with vessel staining with von Willebrand Factor (DAB-enhanced; brown) (nuclei were stained with hematoxylin (blue)) (g ₁). The ipsilateral hypothalamic region exhibited a low value on the ΔR ₂^*/ΔR ₂ map, indicating a low vessel diameter. A high Q value was observed in this area (f), indicative of an enhanced MVD, which was confirmed by histology (g ₄). Contralaterally, normal vessel size (g ₂) and density (g ₅) were observed (R ₂, R ₂^*, ΔR ₂ and ΔR ₂^* are in units sec⁻¹, Q is in units sec^−1/3)

Fig. 5

Maps of K _i and T ₂^* at different time points (1 day–6 weeks) after unilateral embolic stroke in a saline–treated control rat (C) and in a sildenafil-treated rat (T). In the control rat (first row), K _i inside the lesion was elevated from 1 week on, indicative of BBB disruption, which peaked between 2 and 5 weeks after stroke. In a rat treated with angiogenesis-promoting sildenafil (second row), increase of K _i was observed earlier and lasted shorter. Red arrows indicate significantly increased K _i values. In these presumably angiogenic regions, T ₂^* values were significantly decreased, at 4 or 2 weeks after stroke in saline- (third row) and sildenafil-treated rats (fourth row), respectively. Red arrows indicate significantly decreased T ₂^* values. Reproduced from Ref. [33] with permission from Lippincott Williams and Wilkins