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Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease.

ABSTRACT: Moyamoya disease is a rare steno-occlusive cerebrovascular disorder often resulting in hemorrhagic and ischemic strokes. Although sharing the same ischemic stimulus with atherosclerotic cerebrovascular disease, Moyamoya disease is characterized by a highly instable cerebrovascular system which is prone to rupture due to pathological neovascularization. To understand the molecular mechanisms underlying this instability, angiopoietin-2 gene expression was analyzed in middle cerebral artery lesions obtained from Moyamoya disease and atherosclerotic cerebrovascular disease patients. Angiopoietin-2 was significantly up-regulated in Moyamoya vessels, while serum concentrations of soluble angiopoietins were not changed. For further evaluations, cerebral endothelial cells incubated with serum from these patients in vitro were applied. In contrast to atherosclerotic cerebrovascular disease serum, Moyamoya disease serum induced an angiopoietin-2 overexpression and secretion, accompanied by loss of endothelial integrity. These effects were absent or inverse in endothelial cells of non-brain origin suggesting brain endothelium specificity. The destabilizing effects on brain endothelial cells to Moyamoya disease serum were partially suppressed by the inhibition of angiopoietin-2. Our findings define brain endothelial cells as the potential source of vessel-destabilizing factors inducing the high plasticity state and disintegration in Moyamoya disease in an autocrine manner. We also provide new insights into Moyamoya disease pathophysiology that may be helpful for preventive treatment strategies in future.

SUBMITTER: Blecharz KG

PROVIDER: S-EPMC5453470 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease.

Blecharz Kinga G KG Frey Dietmar D Schenkel Tobias T Prinz Vincent V Bedini Gloria G Krug Susanne M SM Czabanka Marcus M Wagner Josephin J Fromm Michael M Bersano Anna A Vajkoczy Peter P

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160101 4

Moyamoya disease is a rare steno-occlusive cerebrovascular disorder often resulting in hemorrhagic and ischemic strokes. Although sharing the same ischemic stimulus with atherosclerotic cerebrovascular disease, Moyamoya disease is characterized by a highly instable cerebrovascular system which is prone to rupture due to pathological neovascularization. To understand the molecular mechanisms underlying this instability, angiopoietin-2 gene expression was analyzed in middle cerebral artery lesions ...[more]

PMID: 27381827

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Project description:Moyamoya disease and cerebrovascular atherosclerotic disease are both chronic ischemic diseases with similar presentations of vascular cognitive impairment. The aim of the present study was to investigate the patterns of microstructural damage associated with vascular cognitive impairment in the two diseases. The study recruited 34 patients with moyamoya disease (age 43.9 ± 9.2 years; 20 men and 14 women, 27 patients with cerebrovascular atherosclerotic disease (age: 44.6 ± 7.6 years; 17 men and 10 women), and 31 normal controls (age 43.6 ± 7.3 years; 18 men and 13 women) from Huashan Hospital of Fudan University in China. Cognitive function was assessed using the Mini-Mental State Examination, long-term delayed recall of Auditory Verbal Learning Test, Trail Making Test Part B, and the Symbol Digit Modalities Test. Single-photon emission-computed tomography was used to examine cerebral perfusion. Voxel-based morphometry and tract-based spatial statistics were performed to identify regions of gray matter atrophy and white matter deterioration in patients and normal controls. The results demonstrated that the severity of cognitive impairment was similar between the two diseases in all tested domains. Patients with moyamoya disease and those with cerebrovascular atherosclerotic disease suffered from disturbed supratentorial hemodynamics. Gray matter atrophy in bilateral middle cingulate cortex and parts of the frontal gyrus was prominent in both diseases, but in general, was more severe and more diffuse in those with moyamoya disease. White matter deterioration was significant for both diseases in the genu and body of corpus callosum, in the anterior and superior corona radiation, and in the posterior thalamic radiation, but in moyamoya disease, it was more diffuse and more severe. Vascular cognitive impairment was associated with regional microstructural damage, with a potential link between, gray and white matter damage. Overall, these results provide insight into the pathophysiological nature of vascular cognitive impairment. This study was approved by the Institutional Review Board in Huashan Hospital, China (approval No. 2014-278). This study was registered with ClinicalTrials.gov on December 2, 2014 with the identifier NCT02305407.

Project description:BACKGROUND:Surgical revascularization is often performed in patients with moyamoya, however routine tools for efficacy evaluation are underdeveloped. The gold standard is digital subtraction angiography (DSA); however, DSA requires ionizing radiation and procedural risk, and therefore is suboptimal for routine surveillance of parenchymal health. OBJECTIVE:To determine whether parenchymal vascular compliance measures, obtained noninvasively using magnetic resonance imaging (MRI), provide surrogates to revascularization success by comparing measures with DSA before and after surgical revascularization. METHODS:Twenty surgical hemispheres with DSA and MRI performed before and after revascularization were evaluated. Cerebrovascular reactivity (CVR)-weighted images were acquired using hypercapnic 3-Tesla gradient echo blood oxygenation level-dependent MRI. Standard and novel analysis algorithms were applied (i) to quantify relative CVR (rCVRRAW), and decompose this response into (ii) relative maximum CVR (rCVRMAX) and (iii) a surrogate measure of the time for parenchyma to respond maximally to the stimulus, CVRDELAY. Measures between time points in patients with good and poor surgical outcomes based on DSA-visualized neoangiogenesis were contrasted (signed-rank test; significance: 2-sided P < .050). RESULTS:rCVRRAW increases (P = .010) and CVRDELAY decreases (P = .001) were observed pre- vs post-revascularization in hemispheres with DSA-confirmed collateral formation; no difference was found pre- vs post-revascularization in hemispheres with poor revascularization. No significant change in rCVRMAX post-revascularization was observed in either group, or between any of the MRI measures, in the nonsurgical hemisphere. CONCLUSION:Improvement in parenchymal compliance measures post-revascularization, primarily attributed to reductions in microvascular response time, is concurrent with collateral formation visualized on DSA, and may be useful for longitudinal monitoring of surgical outcomes.

Project description:BACKGROUND AND PURPOSE:There is a critical need for a reliable and clinically feasible imaging technique that can enable prognostication and selection for revascularization surgery in children with Moyamoya disease. Blood oxygen level-dependent MR imaging assessment of cerebrovascular reactivity, using voluntary breath-hold hypercapnic challenge, is one such simple technique. However, its repeatability and reliability in children with Moyamoya disease are unknown. The current study sought to address this limitation. MATERIALS AND METHODS:Children with Moyamoya disease underwent dual breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging of cerebrovascular reactivity in the same MR imaging session. Within-day, within-subject repeatability of cerebrovascular reactivity estimates, derived from the blood oxygen level-dependent signal, was computed. Estimates were associated with demographics and intellectual function. Interrater reliability of a qualitative and clinically applicable scoring scheme was assessed. RESULTS:Twenty children (11 males; 12.1 ± 3.3 years) with 30 MR imaging sessions (60 MR imaging scans) were included. Repeatability was "good" on the basis of the intraclass correlation coefficient (0.70 ± 0.19). Agreement of qualitative scores was "substantial" (κ = 0.711), and intrarater reliability of scores was "almost perfect" (κ = 0.83 and 1). Younger participants exhibited lower repeatability (P = .027). Repeatability was not associated with cognitive function (P > .05). However, abnormal cerebrovascular reactivity was associated with slower processing speed (P = .015). CONCLUSIONS:Breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging is a repeatable technique for the assessment of cerebrovascular reactivity in children with Moyamoya disease and is reliably interpretable for use in clinical practice. Standardization of such protocols will allow further research into its application for the assessment of ischemic risk in childhood cerebrovascular disease.

Dataset Information

Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease.

Publications

Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease.

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