Abstract
Treating the vascular elements within the neurovascular unit is essential for protecting and repairing the brain after stroke. Acute injury on endothelial systems results in the disruption of blood-brain barrier (BBB), while post-ischemic angiogenesis plays an important role in delayed functional recovery. Here, we considered alterations in microvessel integrity to be targets for brain recovery, and tested the natural compound morroniside as a therapeutic approach to restore the vascular elements of injured tissue in a rat model of focal cerebral ischemia. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) model, and morroniside was then administered intragastrically once a day at doses of 30, 90, and 270 mg/kg. BBB integrity and associated factors were analyzed to identify cerebrovascular permeability 3 days after MCAO. The recruitment of endothelial progenitor cells (EPCs), the expression of angiogenic factors and the new vessel formation in the peri-infarct cortex of rats were examined 7 days after MCAO to identify the angiogenesis. We demonstrated that at 3 days post-ischemia, morroniside preserved neurovascular unit function by ameliorating BBB injury. By 7 days post-ischemia, morroniside amplified angiogenesis, in part by enhancing endothelial progenitor cell proliferation and expression of angiogenic factors. Morever, the increase in the amount of vWF+ vessels induced by ischemia could be extended to 28 days after administration of morroniside, indicating the crucial role of morroniside in angiogenesis during the chronic phase. Taken together, our findings suggested that morroniside might offer a novel therapeutic approach for promoting microvascular integrity recovery and provide a thoroughly new direction for stroke therapy.
Highlights
Ischemic stroke is the most common form of stroke and is caused by the abrupt interruption of blood flow to the brain [1,2]
In order to provide the direct evidence whether morroniside could protect the blood–brain barrier (BBB) function, Evans Blue dye was used to assess BBB integrity at 72 h after middle cerebral artery occlusion (MCAO)
The results indicated that Evans Blue extravasation was increased by approximately 1.1-fold in ischemic rats compared to the sham-operated group, indicating the disruption of BBB (Figure 1A)
Summary
Ischemic stroke is the most common form of stroke and is caused by the abrupt interruption of blood flow to the brain [1,2]. The relevance of dynamic interactions between cerebral endothelial cells, astrocytes, pericytes and neurons is emphasized for brain function and dysfunction after stroke. During the early acute phase after stroke onset, besides basic cell death mechanisms, one of the most important facets of neurovascular damage is manifested as disruptions of blood–brain barrier (BBB) function [3,4]. BBB breakdown is represented by the disruption of endothelial astrocyte-matrix interactions and leads to transmigration of inflammatory cells as well as toxic molecules into the brain parenchyma, which results in cerebral edema and hemorrhage [5]. Angiogenesis is an important process in forming the new brain microvessels after cerebral ischemia, which can improve tissue microperfusion within the ischemic boundary region [7]. For vascular elements within the neurovascular unit, it is believed that the alterations in microvessel integrity might be targets for BBB function recovery, including cerebrovascular permeability during the early phase and the angiogenesis process during the late phase [13]
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