Netrin-4 Enhances Angiogenesis and Neurologic Outcome after Cerebral Ischemia

Functional recovery after cerebral ischemia is mediated by the regeneration of vascular networks and the restoration of synaptic architecture. Netrins have been implicated in neuronal pathfinding and angiogenesis. In this study, we investigated the expression of Netrin-4 and its putative receptors, deleted in colorectal cancer (DCC), Unc5A, and Unc5B after distal middle cerebral artery occlusion in mice. Netrin-4 protein was also administered intracerebroventricularly to examine its effect on angiogenesis and behavioral recovery. Netrin-4 protein was highly upregulated in the ischemic core as soon as 1 day after cerebral ischemia, with subsequent downregulation after 1 week. Its expression was limited to the area of blood—brain barrier damage and was seen on both blood vessels and astrocytic foot processes. Although there was not a significant upregulation of the putative Netrin-4 receptor Unc5A and Unc5B, there was a significant increase in expression of the DCC receptor on neuronal processes in the peri-infarct cortex. Intracerebroventricular administration of Netrin-4 into the ischemic brain increased blood vessel density, endothelial proliferation, and improved behavioral recovery at 1 week after stroke, but did not have an effect on blood—brain barrier permeability or infarct size. These findings suggest that Netrin-4 may improve poststroke functional recovery by enhancing blood vessel proliferation.

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.116.308620 ◽

2017 ◽

Vol 37 (5) ◽

pp. 867-878 ◽

Cited By ~ 22

Author(s):

Adnan Ghori ◽

Florian B. Freimann ◽

Melina Nieminen-Kelhä ◽

Irina Kremenetskaia ◽

Karen Gertz ◽

...

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Major Complication ◽

Artery Occlusion ◽

Brain Barrier ◽

Tyrosine Kinase Receptor ◽

Vascular Repair ◽

Brain Swelling ◽

Blood Brain ◽

Repair Mechanisms

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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Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.59 ◽

2008 ◽

Vol 28 (10) ◽

pp. 1674-1685 ◽

Cited By ~ 86

Author(s):

Motoaki Fujimoto ◽

Yasushi Takagi ◽

Tomohiro Aoki ◽

Makoto Hayase ◽

Takeshi Marumo ◽

...

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Vasogenic Edema ◽

Ischemic Injury ◽

Artery Occlusion ◽

Brain Barrier ◽

Tissue Inhibitor ◽

Blood Brain ◽

Significant Difference

Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood—brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1−/−and TIMP-2−/− mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1−/− mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.

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Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke

ASN NEURO ◽

10.1177/1759091420961612 ◽

2020 ◽

Vol 12 ◽

pp. 175909142096161

Author(s):

Daniela F. Goncalves ◽

Monica S. Guzman ◽

Robert Gros ◽

André R. Massensini ◽

Robert Bartha ◽

...

Keyword(s):

Blood Brain Barrier ◽

Functional Recovery ◽

Functional Outcomes ◽

Artery Occlusion ◽

Brain Barrier ◽

Lesion Volume ◽

Functional Impairments ◽

Ach Release ◽

Cholinergic Interneurons ◽

Blood Brain

Acetylcholine (ACh) has been suggested to facilitate plasticity and improve functional recovery after different types of brain lesions. Interestingly, numerous studies have shown that striatal cholinergic interneurons are relatively resistant to acute ischemic insults, but whether ACh released by these neurons enhances functional recovery after stroke is unknown. We investigated the role of endogenous striatal ACh in stroke lesion volume and functional outcomes following middle cerebral artery occlusion to induce focal ischemia in striatum-selective vesicular acetylcholine transporter-deficient mice (stVAChT-KO). As transporter expression is almost completely eliminated in the striatum of stVAChT-KO mice, ACh release is nearly abolished in this area. Conversely, in other brain areas, VAChT expression and ACh release are preserved. Our results demonstrate a larger infarct size after ischemic insult in stVAChT-KO mice, with more pronounced functional impairments and increased mortality than in littermate controls. These changes are associated with increased activation of GSK-3, decreased levels of β-catenin, and a higher permeability of the blood–brain barrier in mice with loss of VAChT in striatum neurons. These results support a framework in which endogenous ACh secretion originating from cholinergic interneurons in the striatum helps to protect brain tissue against ischemia-induced damage and facilitates brain recovery by supporting blood–brain barrier function.

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