Dynamic Changes in Vascular Permeability, Cerebral Blood Volume, Vascular Density, and Size after Transient Focal Cerebral Ischemia in Rats: Evaluation with Contrast-Enhanced Magnetic Resonance Imaging

Abstract

Postischemic cerebral blood flow and blood volume changes have been associated with angiogenesis; nevertheless, the spatiotemporal changes in vascular permeability, vascular density, and vessel size have not been investigated. Here we report a prolonged increase in vascular permeability from day 3 to day 21 after ischemia, in particular in the reperfused outer cortical layers and leptomeninges. Increased cerebral blood volume (CBV) was observed from day 3 to day 14, whereas increased blood volume in small vessels, primarily capillaries, was noticed from day 7 to day 14 in the reperfused cortex. An initial decrease in vascular density and a reciprocal increase in vessel size were observed within the reperfused cortex at days 1 and 3 after ischemia. Immunohistological analysis confirmed a similar decrease in microvessel density and an increase in vessel size in vessels with a diameter greater than 30 microm. These large-sized vessels exhibited intense basic fibroblast growth factor and endothelial nitric oxide synthase immunoreactivity, suggesting the growth of collateral vessels. By contrast, a late increase in vascular density was noticed in the reperfused outer cortex at days 14 and 21 after ischemia. Together, these findings suggest that the early phase of CBV increase is likely because of the improvement in collateral circulation, whereas the late phase of CBV increase is attributed to the surge of angiogenesis.

Chronic Hyperperfusion and Angiogenesis Follow Subacute Hypoperfusion in the Thalamus of Rats with Focal Cerebral Ischemia

“…Both techniques have been validated for the study of focal ischemia in rodents (Bratane et al, 2010). Arterial spin labeling (Jiang et al, 1998) and dynamic susceptibility contrast MRI (Rudin et al, 2001;Lin et al, 2008) have shown prolonged cortical and striatal hypoperfusion after permanent middle cerebral artery occlusion in rats, which is consistent with studies using autoradiography or laser Doppler flowmetry (Bolander et al, 1989;Borlongan et al, 2004;Li et al, 2007;Eve et al, 2009). Relatively few studies have looked beyond the first few days after injury and at regions outside the primary infarct, although knowledge of how the cerebral blood supply adapts long after ischemic injury may aid our understanding of brain recovery processes.…”

Vessel Size Imaging Reveals Pathological Changes of Microvessel Density and Size in Acute Ischemia

“…Reduced Q values in patients 12 and 13 fit to the decreased Q in the ischemic tissue in rats after transient focal ischemia (Lin et al, 2008). The values of Q and VSI vary among patients owing to different territories being involved in ischemia for each patient.…”

“…This novel technique has recently been applied to animal ischemic stroke models (Bosomtwi et al, 2008;Lin et al, 2008). Because of a much faster blood circulation in rodent models, these two studies used ssCE-MRI, which uses DR 2GE and DR 2SE before and after administration of an intravascular contrast agent, and thus fails to provide CBV evaluation and VSI validation.…”

In Vivo Imaging of Neurovascular Remodeling After Stroke

“…Elevated Ki in the first weeks after stroke in rats has been observed in ischemic border zone areas where vascular density was chronically increased. 24,25 However, it is important to note that BBB leakage may not solely reflect an early state of effective angiogenesis. BBB breakdown, particularly at early stages, also is a direct feature of ischemia-induced endothelial injury.…”