Can angiogenesis be exploited to improve stroke outcome? Mechanisms and therapeutic potential

Slevin, Mark; Kumar, Patricia; Gaffney, John; Kumar, Shant; Krupiński, Jerzy

doi:10.1042/cs20060049

Cited by 136 publications

(137 citation statements)

References 137 publications

(146 reference statements)

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“…31 However, angiogenesis alone would have less impact on repair, if the BBB is not restabilized. In this study, we present insights into the integral role of pericytes in the normal course of endogenous BBB recovery after cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

Ghori

Freimann

Nieminen-Kelhä

et al. 2017

ATVB

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Objective— Cerebral edema caused by the disruption of the blood–brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood–brain barrier restoration after mild cerebral ischemia occlusion/reperfusion. Approach and Results— Here, we show that the guidance molecule ephrinB2 plays a key role in neurovascular protection and blood–brain barrier restoration after stroke. In a focal stroke model, we characterize the stroke-induced damage to cerebral blood vessels and their subsequent endogenous repair on a cellular, molecular, and functional level. EphrinB2 and its tyrosine kinase receptor EphB4 are upregulated early after stroke by endothelial cells and perivascular support cells, in parallel to their reassembly during neurovascular recovery. Using both retroviral and pharmacological approaches, we show that the inhibition of ephrinB2/EphB4 signaling suppresses post-middle cerebral artery occlusion neurovascular repair mechanisms resulting in an aggravation of brain swelling. In contrast, the activation of ephrinB2 after brain ischemia leads to an increased pericyte recruitment and increased endothelial–pericyte interaction, resulting in an accelerated neurovascular repair after ischemia. Conclusions— We show that reducing swelling could result in improved outcome because of reduction in damaged brain tissue. We also identify a novel role for ephrinB2/EphB4 signaling in the maintenance of the neurovascular homeostasis and provide a novel therapeutic approach in reducing brain swelling after stroke.

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Section: Discussionmentioning

confidence: 99%

EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

Ghori

Freimann

Nieminen-Kelhä

et al. 2017

ATVB

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“…36 Furthermore, angiogenesis is considered a key feature of ischemic stroke recovery and neuronal post-stroke re-organization. 37 Several studies using experimental stroke models have indicated the beneficial effects of glibenclamide administration after reperfusion, such as reversing ischemia-reperfusion injury by halting oxidative stress and inflammation in the hippocampus, 9 preventing cytotoxic edema after cerebral ischemia, 2,3,1,7 and enhancing neuroprotection, which all eventually lead to a better functional outcome. 8 Thus, although glibenclamide did not modify the size and cell density of microglia nor astroglia after ischemia here, it enhanced long-term brain repair processes and functional recovery outcomes of the rats.…”

Section: Discussionmentioning

confidence: 99%

Glibenclamide Enhances Neurogenesis and Improves Long-Term Functional Recovery after Transient Focal Cerebral Ischemia

Ortega

Jolkkonen

Mahy

et al. 2012

J Cereb Blood Flow Metab

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Glibenclamide is neuroprotective against cerebral ischemia in rats. We studied whether glibenclamide enhances long-term brain repair and improves behavioral recovery after stroke. Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 minutes. A low dose of glibenclamide (total 0.6 mg) was administered intravenously 6, 12, and 24 hours after reperfusion. We assessed behavioral outcome during a 30-day follow-up and animals were perfused for histological evaluation. In vitro specific binding of glibenclamide to microglia increased after pro-inflammatory stimuli. In vivo glibenclamide was associated with increased migration of doublecortin-positive cells in the striatum toward the ischemic lesion 72 hours after MCAO, and reactive microglia expressed sulfonylurea receptor 1 (SUR1) and Kir6.2 in the medial striatum. One month after MCAO, glibenclamide was also associated with increased number of NeuN-positive and 5-bromo-2-deoxyuridine-positive neurons in the cortex and hippocampus, and enhanced angiogenesis in the hippocampus. Consequently, glibenclamide-treated MCAO rats showed improved performance in the limb-placing test on postoperative days 22 to 29, and in the cylinder and water-maze test on postoperative day 29. Therefore, acute blockade of SUR1 by glibenclamide enhanced long-term brain repair in MCAO rats, which was associated with improved behavioral outcome.

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“…Other avenues of study are directed to the development of derivations of EPO to reduce erythropoietic activity and the potential associated vascular complications (Montero et al, 2007). Yet, these lines of investigation are not without limitations, since chemical derivatives of EPO can become absent of clinical efficacy as well as possibly lose the ability to promote sustainable cytoprotective effects, such as neurogenesis (Gonzalez et al, 2007) and angiogenesis Reinders et al, 2006;Slevin et al, 2006;Zhang and Ma, 2007).…”

Section: Future Perspectives and Considerations For Epomentioning

confidence: 99%

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

Maiese

Chong

et al. 2008

Progress in Neurobiology

102

155

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Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.

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Can angiogenesis be exploited to improve stroke outcome? Mechanisms and therapeutic potential

Cited by 136 publications

References 137 publications

EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

Glibenclamide Enhances Neurogenesis and Improves Long-Term Functional Recovery after Transient Focal Cerebral Ischemia

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

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