Blood—Brain Barrier Breakdown Involves Four Distinct Stages of Vascular Damage in Various Models of Experimental Focal Cerebral Ischemia

Abstract

Ischemic stroke not only impairs neuronal function but also affects the cerebral vasculature as indicated by loss of blood-brain barrier (BBB) integrity. Therefore, therapeutical recanalization includes an enhanced risk for hemorrhagic transformation and bleeding, traditionally attributed to a 'reperfusion injury'. To investigate the mechanisms underlying ischemia-/reperfusion-related BBB opening, we applied multiple immunofluorescence labeling and electron microscopy in a rat model of thromboembolic stroke as well as mouse models of permanent and transient focal cerebral ischemia. In these models, areas exhibiting BBB breakdown were identified by extravasation of intravenously administered fluorescein isothiocyanate (FITC)-albumin. After 24 hours, expression of markers for tight and adherens junctions in areas of FITC-albumin leakage consistently remained unaltered in the applied models. However, lectin staining with isolectin B4 indicated structural alterations in the endothelium, which were confirmed by electron microscopy. While ultrastructural alterations in endothelial cells did not differ between the applied models including the reperfusion scenario, we regularly identified vascular alterations, which we propose to reflect four distinct stages of BBB breakdown with ultimate loss of endothelial cells. Therefore, our data strongly suggest that ischemia-related BBB failure is predominantly caused by endothelial degeneration. Thus, protecting endothelial cells may represent a promising therapeutical approach in addition to the established recanalizing strategies.

Blood−brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury

“…Caveolin-1 mediates this initial BBB opening [38,39]. A comparative analysis of three different models of stroke reveals four stages in acute BBB breakdown: endothelial swelling, endothelial membrane disruption, disruption of tight junction seals between vascular cells and adjacent glia, and complete vascular disruption [40 ▪ ]. …”

Serum Albumin Is Negatively Associated with Hemorrhagic Transformation in Acute Ischemic Stroke Patients

“…Endothelial damage caused by ischemia [26] results in an abnormal increase in BBB permeability, which allows extravasation of blood products into brain tissue, leading to further ischemia, leukocyte migration, and cytokine release [27]. Inflammation and oxidative injuries also increase the risk of HT [4].…”

Translating connexin biology into therapeutics

“…In many cases this is no doubt correct, but after injury, whether trauma, ischaemia, inflammatory cytokine induced or infection and at the edge of chronic wounds, connexin hemichannel mediated vascular leak is prevalent with hemichannel opening leading directly to endothelial cell loss [9,66]. This has been investigated in detail in embolic stroke where there is 'disintegration of the endothelial layer itself, thereby allowing unhindered extravasation of blood-borne molecules at different time points' [67] and in focal cerebral ischaemia where four distinct stages of blood-brain barrier breakdown with ultimate loss of endothelial cells occurs [68]. In areas where there is blood-brain barrier breakdown the endothelium becomes ruffled or discontinuous.…”