Abstract
In the setting of stroke, ischemia-related blood-brain barrier (BBB) dysfunction aggravates the cerebral edema, which critically impacts on the clinical outcome. Further, an impaired vascular integrity is associated with the risk of intracranial bleeding, especially after therapeutic recanalization. Therefore, the present study was aimed to investigate early vascular alterations from 30 min to 4 h after experimental middle cerebral artery occlusion (MCAO) in mice. Here, an extravasation of the permeability marker FITC-albumin was detectable in animals 2 and 4 h after MCAO. Thereby, BBB breakdown correlated with alterations of the endothelial surface, indicated by a discontinuous isolectin-B4 staining, while tight junction strands remained detectable using electron and immunofluorescence microscopy. Noteworthy, already 30 min after MCAO, up to 60% of the ischemia-affected vessels showed an endothelial edema, paralleled by edematous astrocytic endfeet, clearly preceding FITC-albumin extravasation. With increasing ischemic periods, scores of vascular damage significantly increased with up to 60% of the striatal vessels showing loss of endothelial integrity. Remarkably, comparison of permanent and transient ischemia did not provide significant differences 4 h after ischemia induction. As these degenerations also involved penumbral areas of potentially salvageable tissue, adjuvant approaches of endothelial protection may help to reduce the vasogenic edema after ischemic stroke.
Highlights
Ischemic stroke is one of the leading causes of death world-wide and surviving patients often suffer from long-lasting disabilities [47]
blood-brain barrier (BBB) breakdown for Fluorescein isothiocyanate (FITC)-albumin precedes aquaporin-4related astrocyte depolarization Since astrocyte function including expression of Aqp4 water channels is critically involved in edema formation following stroke [42, 54], we further addressed the expression of Aqp4 in the time course of ischemia from 30 min to 4 h after ischemia induction
Deciphering the pathophysiology of the ischemia-affected neurovascular unit’ (NVU) including endothelial dysfunction was rated as high priority for stroke research [15, 44], while further insights will hopefully allow the development of adjuvant therapies which may help to extend the therapeutic time window and to protect BBB function in the setting of stroke
Summary
Ischemic stroke is one of the leading causes of death world-wide and surviving patients often suffer from long-lasting disabilities [47]. Despite the efforts to extend the time window for recanalization of occluded vessels via intravenous thrombolysis [21] and mechanical thrombectomy [6, 50], only a minority of patients is currently eligible for these treatments [1, 13]. Stroke research is complicated by the ‘translational roadblock’, which describes the difficulty to translate preclinical treatment options into the clinical routine. More than 1000 experimental approaches so far failed to be successfully translated from bench to bedside [51]. The need for additional and supportive neuroprotective strategies is still evident.
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