Role of Akt signaling pathway in delayed cerebral vasospasm after subarachnoid hemorrhage in rats

Song, Jin‐Ning; An, Jiyang; Hao, Guangshan; Li, Dan‐Dong; Sun, Peng; Liu, Yu; Xue, Jiao

doi:10.1007/s00701-013-1808-8

Cited by 8 publications

(8 citation statements)

References 19 publications

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“…A previous study indicated that MMP-9 was expressed in the vascular wall and the co-staining for vascular smooth muscle cells showed that the MMP-9 expression localized to the vascular smooth muscle cells after SAH 8 . The switch of vascular smooth muscle phenotype may not markedly affect the size or function of the large arteries in the previous study 1, 31 , but some studies reported that unbalanced contractile/synthetic vascular smooth muscle phenotype affected the size of the cerebral arteries and aggravated brain swelling and brain edema 29,30,32 . It is presumed that due to the limited two or three layers of smooth muscle cells in smaller arteries, vascular smooth muscle phenotype change causes the loss of small arteries vascular tone and affects BBB and autoregualtion.…”

Section: Discussionmentioning

confidence: 82%

Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Zhang

Yang

et al. 2016

Stroke

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Background and Purpose Recombinant Osteopontin (rOPN) has been reported to be neuroprotective in stroke animal models. The purpose of this study is to investigate a potential role and mechanism of nasal administration of rOPN on preserving the vascular smooth muscle phenotype in early brain injury after SAH. Methods One hundred and ninety-two male adult Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Integrin-linked kinase (ILK) siRNA was intracerebroventricularly injected 48 hours before SAH. The integrin receptor antagonist GRGDSP, FAK inhibitor Fib-14 and Rac-1 inhibitor NSC23766 were administered 1 hour before SAH induction. rOPN was administered via the intracerebroventricular and nasal route after SAH. SAH grade, neurological scores, brain water content, brain swelling, hematoxylin and eosin staining, India ink angiography, Western blots, and immunofluorescence were used to study the mechanisms of rOPN on the vascular smooth muscle phenotypic transformation. Results The marker protein of vascular smooth muscle phenotypic transformation alpha-SMA decreased and SMemb increased significantly at 24 and 72 hours in the cerebral arteries after SAH. rOPN prevented changes of alpha-SMA and SMemb, and significantly alleviated neurobehavioral dysfunction, increased the cross-section area and the lumen diameter of the cerebral arteries, reduced brain water content and brain swelling and improved the wall thickness of cerebral arteries. These effects of rOPN were abolished by GRGDSP, ILK siRNA and NSC23766. Intranasal application of rOPN at 3 hrs after SAH also reduced neurological deficits. Conclusions rOPN prevented the vascular smooth muscle phenotypic transformation and improved the neurological outcome, which was possibly mediated by the integrin receptor/ILK/Rac-1 pathway.

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Section: Discussionmentioning

confidence: 82%

Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Zhang

Yang

et al. 2016

Stroke

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“…The ratio of the ratios for the light-exposed and the nonlight-exposed groups were found to be significantly different (p < 0.001) (►Figs. [4][5][6].…”

Section: Analysis Of the Photographs And Artery Diameter Measurementsmentioning

confidence: 99%

“…Since cerebral vasospasm (CV) was first recognized in 1951, many different theories have been proposed to explain its pathophysiology. [1][2][3][4][5] Some of these theories were negated in both clinical and experimental studies; the remainder failed to succeed clinically despite showing promising results in experimental studies. 6,7 Nitric oxide (NO) is made by the endothelial nitric oxide synthase (eNOS) in the intima and by the neuronal nitric oxide synthase (nNOS) in the adventitia of cerebral vessels.…”

Section: Introductionmentioning

confidence: 99%

Effect of Visible Light on Vasospasticity of Post–Subarachnoid Hemorrhage Cerebrospinal Fluid

Sabancı

Omay

Aras

et al. 2017

J Neurol Surg A Cent Eur Neurosurg

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Cerebral vasospasm (CV) is a serious complication of subarachnoid hemorrhage (SAH) with high morbidity and mortality rates. The mechanism of CV has not been determined. There are many theories related to this unsolved issue, one of which supports CV as a two-stage phenomenon from a pathophysiologic perspective. The first stage consists of inhibition of neuronal nitric oxide synthase by oxyhemoglobin, which results in a decrease of nitric oxide (NO) production. The second stage consists of an increase in the levels of asymmetric dimethylarginine through bilirubin oxidation products (BOXes), which are oxidized by-products of hemoglobin metabolism. These in turn inhibit endothelial nitric oxide synthase (eNOS), which results in the blockage of the second NO production mechanism. BOXes are sensitive to visible light, as is their precursor bilirubin. The hypothesis of CV prevention using the photosensitivity of BOXes was tested in this study. Cerebrospinal fluid (CSF) obtained from two patients with SAH was divided in half and either exposed to a standard dose of visible light or not exposed to any light. The CSF was spectrophotometrically investigated and the concentration of BOXes was measured. A comparison between CSF samples exposed to light and not exposed to light was made. Using two groups of 16 rats each, the vasospastic effect of the CSF exposed and not exposed to light on arteries of the cortical surface was measured. The cortex was exposed using the cranial window. Spectrophotometric analysis revealed that the concentration of BOXes in the CSF decreased significantly after being exposed to visible light ( < 0.001). There was a significant difference of the vasospastic effect of CSF on exposed cortical arteries ( < 0.001). The concentration of BOXes and the vasospastic effect of CSF taken from patients with SAH were significantly reduced after being exposed to visible light if compared with CSF not exposed to light.

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“…Apoptotic cell death after GMH may be of multifactorial etiology, mediated by local inflammation, proteases and free radicals. 10, 11 “Expression of the Sphk1/S1PR/Akt pathway beyond 24 hours has not been performed in the GMH model, however in adult experimental subarachnoid hemorrhage the rise in pAkt levels are found to occur in the delayed phase 12 .…”

Section: Discussionmentioning

confidence: 99%

Isoflurane Post-Treatment Ameliorates GMH-Induced Brain Injury in Neonatal Rats

Leitzke

Rolland

Krafft

et al. 2013

Stroke

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Background and Purpose This study investigated whether isoflurane ameliorates neurological sequelae after germinal matrix hemorrhage (GMH) through activation of the cytoprotective sphingosine kinase/sphingosine-1-phosphate receptor/Akt pathway. Methods GMH was induced in P7 rat pups by intraparenchymal infusion of bacterial collagenase (0.3U) into the right hemispheric germinal matrix. GMH animals received 2% isoflurane either once 1 hour after surgery, or every 12 hours for 3 days. Isoflurane treatment was then combined with sphingosine-1-phoshate receptor-1/2 antagonist VPC23019 or sphingosine kinase 1/2 antagonist N,N-dimethylsphingosine. Results Brain protein expression of sphingosine kinase-1 and phosphorylated Akt were significantly increased after isoflurane post-treatment, and cleaved capase-3 was decreased at 24 hours after surgery; which was reversed by the antagonists. Isoflurane significantly reduced post-hemorrhagic ventricular dilation and improved motor, but not cognitive, functions in GMH animals 3 weeks after surgery; no improvements were observed following VPC23019 administration. Conclusion Isoflurane post-treatment improved the neurological sequelae after GMH possibly by activation of the sphingosine kinase/Akt pathway.

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Role of Akt signaling pathway in delayed cerebral vasospasm after subarachnoid hemorrhage in rats

Abstract: These results support a novel mechanism in which the Akt signaling pathway plays an important role in the proliferation of smooth muscle cells (SMCs) rather than inducing phenotype switching in basilar arteries, which promotes the development of DCVS after SAH.

Cited by 8 publications

References 19 publications

Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats

Effect of Visible Light on Vasospasticity of Post–Subarachnoid Hemorrhage Cerebrospinal Fluid

Isoflurane Post-Treatment Ameliorates GMH-Induced Brain Injury in Neonatal Rats

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