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      Remodeling of Cerebral Microcirculation after Ischemia-Reperfusion

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          Clinical and experimental studies have been focused on the pathophysiological mechanisms induced by brain ischemia-reperfusion injury. Recovery events, such as neurogenesis, angiogenesis and the growth of new blood vessels from the preexisting vascular tree, have been intensively studied in the last decades to clarify the vascular remodeling crucial for stroke outcome. This review aims to discuss the cerebral microcirculation remodeling induced by ischemia-reperfusion and the mechanisms involved in angiogenesis and vasculogenesis. The first in vivo observations were focused on anastomotic shunting of cerebral blood flow (CBF) in experimental and clinical models. Thereafter, vascular remodeling induced by cerebral ischemia-reperfusion was reported in mice and rats. Successively, other studies have assessed that within 30 days of middle cerebral artery (MCA) occlusion in rats, there is an increase in CBF and recovery from stroke. Recently, rats submitted to transient MCA occlusion showed pial microcirculation remodeling with the formation of new arterioles sprouting from penumbra vessels and overlapping the ischemic core. This review focuses on the production and/or activation of vasculotrophic factors able to trigger and facilitate microvascular remodeling. Vascular endothelial growth factor and endothelium-released nitric oxide appear to be the main factors involved in the formation of new vessels during microvascular remodeling. These studies are fundamental for consequent interventions on molecular targets, useful for fostering vascular remodeling and the recovery of functions.

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          Most cited references 61

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          Induction of reproducible brain infarction by photochemically initiated thrombosis.

          We have used a photochemical reaction in vivo to induce reproducible thrombosis leading to cerebral infarction in rats. After the intravenous injection of rose bengal, a potent photosensitizing dye, an ischemic lesion was formed by irradiating the left parietal convexity of the exposed skull for 20 minutes with green light (560 nm) from a filtered xenon arc lamp. Animals were allowed to survive from 30 minutes to 15 days after irradiation. Early microscopic alterations within the irradiated zone included the formation of thrombotic plugs and adjacent red blood cell stasis within pial and parenchymal vessels. Scanning electron microscopy revealed frequent platelet aggregates adhering to the vascular endothelium, often resulting in vascular occlusion. Carbon-black brain perfusion demonstrated that occlusion of vascular channels progressed after irradiation and was complete within 4 hours. Histopathological examination at 1, 5, and 15 days revealed that the associated infarct evolved reproducibly through several characteristic stages, including a phase of massive macrophage infiltration. Although cerebral infarction in this model is initiated by thrombosis of small blood vessels, the fact that the main pathological features of stroke are consistently reproduced should permit its use in assessing treatment regimens. Further, the capability of producing infarction in preselected cortical regions may facilitate the study of behavioral, functional, and structural consequences of acute and chronic stroke.
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            Role of oxidants in ischemic brain damage.

             Paul K S Chan (1996)
            Oxygen free radicals or oxidants have been proposed to be involved in acute central nervous system injury that is produced by cerebral ischemia and reperfusion. Because of the transient nature of oxygen radicals and the technical difficulties inherent in accurately measuring their levels in the brain, experimental strategies have been focused on the use of pharmacological agents and antioxidants to seek a correlation between the exogenously supplied specific radical scavengers (ie, superoxide dismutase and catalase) and the subsequent protection of cerebral tissues from ischemic injury. However, this strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain barrier permeability, etc) that may cloud the data interpretation. This mini-review will focus on the oxidant mechanisms in cerebral ischemic brain injury by using transgenic and knockout mice as an alternative approach. Transgenic and knockout mutants that either overexpress or are deficient in antioxidant enzyme/protein levels have been successfully produced. The availability of these genetically modified animals has made it possible to investigate the role of certain oxidants in ischemic brain cell damage in molecular fashion. It has been shown that an increased level of CuZn-superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in CuZn-superoxide dismutase or mitochondrial Mn-superoxide dismutase exacerbates ischemic brain damage. Target disruption of neuronal nitric oxide synthase in mice also provides neuronal protection against permanent and transient focal cerebral ischemia. I conclude that molecular genetic approaches in modifying antioxidant levels in the brain offer a unique tool for understanding the role of oxidants in ischemic brain damage.
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              Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum.

              Recent studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after various insults. However, the precise mechanism of insult-induced neurogenesis has not been demonstrated. In the normal brain, GFAP-expressing cells in the subventricular zone (SVZ) of the lateral ventricles include a neurogenic cell population that gives rise to olfactory bulb neurons only. Herein, we report evidence that, after a stroke, these cells are capable of producing new neurons outside the olfactory bulbs. SVZ GFAP-expressing cells labeled by a cell-type-specific viral infection method were found to generate neuroblasts that migrated toward the injured striatum after middle cerebral artery occlusion. These neuroblasts in the striatum formed elongated chain-like cell aggregates similar to those in the normal SVZ, and these chains were observed to be closely associated with thin astrocytic processes and blood vessels. Finally, long-term tracing of the green fluorescent-labeled cells with a Cre-loxP system revealed that the SVZ-derived neuroblasts differentiated into mature neurons in the striatum, in which they expressed neuronal-specific nuclear protein and formed synapses with neighboring striatal cells. These results highlight the role of the SVZ in neuronal regeneration after a stroke and its potential as an important therapeutic target for various neurological disorders.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                June 2015
                21 April 2015
                : 52
                : 1
                : 22-31
                Department of Clinical Medicine and Surgery, ‘Federico II' University Medical School, Naples, Italy
                Author notes
                *Antonio Colantuoni, MD, Department of Clinical Medicine and Surgery, ‘Federico II' University Medical School, Via S. Pansini, 5, IT-80121 Naples (Italy), E-Mail
                381096 J Vasc Res 2015;52:22-31
                © 2015 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 90, Pages: 10


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