Aberrant Angiogenic Characteristics of Human Brain Arteriovenous Malformation Endothelial Cells (original) (raw)
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Cell Biochemistry and Biophysics, 2014
To compare the mRNA level of angiogenic factor vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2, and MMP-9 in cultured human brain arteriovenous malformation (AVM) endothelial cells (ECs) and normal brain endothelial cells (BECs). Tissue explants both from deformed vessels of AVM and normal microvessel were put into culture for endothelial cells. After the monolayer adherent ECs reached confluence, they were tested with endothelial specific marker CD34 and von Willebrand factor (vWF) by immunochemical assay. mRNA levels of VEGF-A, MMP-2, and MMP-9 in AVM endothelial cells (AVMECs) and BECs were measured by PCR. Immunostaining confirmed that more than 95 % of the cultured cells were CD34 (Fig. 1b) and/or vWF positive. Expression levels of VEGF-A and MMP-2 mRNAs were significantly higher in AVMECs than in BECs. The MMP-9 level was also increased in AVMECs, but the difference was not statistically significant. Vascular tissue explants adherent method is a better approach for isolation and culture of AVMECs. Cultured AVMECs expressed higher angiogenic factors (VEGF, MMP-2) than the controlled BECs, implicating angiogenesis plays an important role in the pathogenesis of AVM.
Endothelial cells in the context of brain arteriovenous malformations
Journal of Clinical Neuroscience, 2011
A subset of brain arteriovenous malformations (AVM) cannot be treated using today's treatment paradigms. Novel therapies may be developed, however, as the underlying pathophysiology of these lesions becomes better understood. Endothelial cells (EC) are the subject of new biological therapies, such as radiosensitisation and vascular targeting. This work reviews the current research surrounding EC in the context of brain AVM, including both in vitro and AVM specimen analysis, with a particular focus on the effect of radiation on EC. EC are heterogeneous with no recognised common phenotype, which leads to difficulties in applying the results of the common studies using human umbilical vein endothelial cells to AVM research. Human brain EC are observed to have a high rate of proliferation and also have a reduced apoptotic response to inflammatory mediators such as transforming growth factor-beta. The angiogenic factors vascular endothelial growth factor and endothelin-1 (ET-1) are not normally produced by quiescent brain vasculature, but are produced by AVM EC. Radiation causes EC to separate and become disrupted. Leucocyte and platelet adherence is increased for several days post-irradiation due to increased E-selectin and P-selectin and intercellular adhesion molecule-1 expression. ET-1 is highly expressed in irradiated AVM EC. Radiosurgery produces local radiation-induced changes in EC, which may allow these changes to be harnessed in conjunction with other techniques such as vascular targeting.
Journal of neurointerventional surgery, 2016
Angiogenesis has a key role in the formation and evolution of brain arteriovenous malformations (AVMs). Numerous models have been developed aiming to recreate configuration of brain AVMs. To develop an animal model sharing the same pathological characteristics as human brain AVMs. Ten pigs were divided into two groups. Five animals underwent endovascular left common carotid artery (CCA) and external carotid artery (ECA) occlusion and five animals served as controls. DSA, associated with 3D-rotational angiography, was performed at day 0 and at 3 months in both groups. The volume of the retia was calculated. Vascular endothelial growth factor (VEGF)-A serum levels were measured in both groups at the same time intervals. Finally, the animals were sacrificed at 3 months and the retia were harvested for pathological and immunohistochemistry examinations. At 3 months, a significantly higher rete volume was seen in group A than in group B (2.92±0.33 mL vs 1.87±0.69 mL, respectively; p=0.01...
Cultured Endothelial Cells From Human Arteriovenous Malformations Have Defective Growth Regulation
Blood, 1999
Vascular malformations are frequent in newborns, and they persist throughout life, which differentiates them from vascular tumors (eg, hemangiomas). Arteriovenous malformations are high-flow vascular malformations. They are considered nonmalignant but can expand and become a significant clinical risk when extensive. To characterize endothelial cells from arteriovenous malformations (AMEC), we cultured cells obtained from surgical specimens and studied their properties. After selection, the cells that grew out from explants had phenotypic and antigenic features (platelet endothelial cell adhesion molecule, von Willebrand factor) of human endothelial cells. Their spontaneous proliferation rate was higher (1.8 to 6.4 times) than that of human umbilical vein, arterial, or microvascular endothelial cells. The proliferation rate of AMEC was not sensitive to the inhibitory activity of various cytokines (interleukin-1, tumor necrosis factor-␣, transforming growth factor-, Interferon-␥). In basal conditions, intercellular adhesion molecule (ICAM-1) was detected at a higher level of expression (6-to 10-fold) on AMEC, but these cells failed to express E-selectin or the vascular cell adhesion molecule (VCAM-1) after cytokine stimulation. Expression of c-ets-1 proto-oncogene was shown by in situ hybridization. The low response to cytokines, the higher propensity to proliferate, and the ets-1 expression suggest that AMEC have a defective regulation of proliferation that may be due to a reduced apoptotic process.
Analysis of Endoglin Expression in Normal Brain Tissue and in Cerebral Arteriovenous Malformations
Stroke, 2000
Background and Purpose —A high incidence of arteriovenous malformations (AVMs) is associated with hereditary hemorrhagic telangiectasia type 1. Endoglin, the gene mutated in this disorder, is expressed at reduced levels on blood vessels of these patients. Since endoglin is a component of the transforming growth factor-β receptor complex critical for vascular development and homeostasis, we determined its expression in sporadic cerebral AVMs and in normal brain vessels. Methods —Twenty cerebral AVMs and 10 normal brain samples were analyzed for endoglin, platelet endothelial cell adhesion molecule 1 (PECAM-1), α-smooth muscle cell actin, vimentin, and desmin by immunohistochemistry. Results —In normal brain, endoglin was found not only on the endothelium of all vessels but also on the adventitial layer of arteries and arterioles. In cerebral AVMs, the numerous vessels present expressed endoglin on both endothelium and adventitia. Arterialized veins, identified by lack of elastin and ...
Neurosurgery, 2011
The management of cerebral arteriovenous malformation (AVM) is challenging, and invasive therapies place vital intracranial structures at risk of injury. The development of noninvasive, pharmacologic approaches relies on identifying factors that mediate key angiogenic processes. Previous studies indicate that endothelial cells (ECs) derived from cerebral AVM (AVM-ECs) are distinct from control brain ECs with regard to important angiogenic characteristics. To determine whether thrombospondin-1 (TSP-1), a potent angiostatic factor, regulates critical angiogenic features of AVM-ECs and to identify factors that modulate TSP-1 production in AVM-ECs. EC proliferation, migration, and tubule formation were evaluated with bromodeoxyuridine incorporation, Boyden chamber, and Matrigel studies, respectively. TSP-1 and inhibitor of DNA binding/differentiation 1 (Id1) mRNA levels were quantified with microarray and quantitative real-time polymerase chain reaction analyses. TSP-1 protein expressio...
Journal of Clinical Neuroscience, 2005
Background. Vascular endothelial growth factor (VEGF) and its tyrosine kinase family of receptors (VEGFR) (Flt-1, Flk-1, Flt-4) have been implicated in vascular angiogenesis and remodelling in cerebral arteriovenous malformations (CAVM). In this study, we investigate the role of hypoxia inducible factor-1 (HIF-1a) in CAVM and its relationship to VEGF and VEGFR. Methods. Surgical specimens from 26 patients undergoing CAVM resection were studied for HIF-1a, VEGF, Flt-1, Flk-1 and Flt-4. The mean age was 34.08+/À14.18 years. Twenty-one patients presented with intracerebral haemorrhage. Results. VEGF, Flt-1 and Flt-4 were expressed in all specimens. Flk-1 was expressed in 15 of 26 patients. HIF-1a was expressed in 15 of 26 patients. HIF-1a expression was significantly associated with VEGF, Flt-1 and Flk-1 expression (p < 0.05). Conclusions. HIF-1a is expressed in human CAVM. The expression of HIF-1a is significantly related to VEGF and VEGFR expression, suggesting a possible role for its induction and role in maintaining angiogenesis and vascular remodelling. ª Summary Cortical neuronal and glial c-fos immunoreactivity has been demonstrated in experimental and human brain injury. c-fos is one of the immediate early genes important in signal transduction linking environmental stimuli to the cellular genome. c-fos immunoreactivity was semiquantitated in a head impact sheep model using a grid system applied to standard coronal brain sections obtained from 12 impacted and 4 control sheep. Substantial glial and neuronal c-fos immunoreactivity was present in the pericontusional (penumbra) region, but was absent or minimal in the core of the contusion. Apart from these focal changes, c-fos immunoreactivity was diffusely distributed, with greater involvement in the cerebrum on the side of impact. In the cerebellum, Bergmann glia showed prominent c-fos immunoreactivity, while Purkinje cells were consistently immunonegative. c-fos immunoreactivity varied in different regions of the brain (focal and diffuse patterns) in this ovine head impact model. ª
Neurosurgical Focus, 2014
Object Arteriovenous malformations (AVMs) are classically described as congenital static lesions. However, in addition to rupturing, AVMs can undergo growth, remodeling, and regression. These phenomena are directly related to cellular, molecular, and physiological processes. Understanding these relationships is essential to direct future diagnostic and therapeutic strategies. The authors performed a search of the contemporary literature to review current information regarding the molecular and cellular biology of AVMs and how this biology will impact their potential future management. Methods A PubMed search was performed using the key words “genetic,” “molecular,” “brain,” “cerebral,” “arteriovenous,” “malformation,” “rupture,” “management,” “embolization,” and “radiosurgery.” Only English-language papers were considered. The reference lists of all papers selected for full-text assessment were reviewed. Results Current concepts in genetic polymorphisms, growth factors, angiopoietin...
2013
IMPORTANCE Endoglin (CD105) and endothelial nitric oxide synthase (eNOS) assist in regulating vascular development. Variation in expression of these factors is linked to errors in vascular growth and remodeling in invasive lesions. OBJECTIVE To clarify the role of endoglin and eNOS in the growth of extracranial head and neck arteriovenous malformations (AVMs), an invasive and high-flow vascular anomaly. DESIGN AND SETTING Immunohistochemistry and Western blot study at an academic research center. SPECIMENS Frozen and formalin-fixed paraffin-processed human AVMs (n = 14) were examined for expression of CD105 and eNOS. Expression in infantile hemangiomas (n = 9) and in normal skin with subcutaneous tissue (n = 9) was used for comparison. MAIN OUTCOME MEASURES Quantitative assessment and localization of CD105 and eNOS protein expression were performed on each specimen by immunohistochemistry and Western blot analysis. Protein expression levels were compared with β-actin level and were ...
Inflammatory molecule expression in cerebral arteriovenous malformations
Journal of Clinical …, 2008
Inflammatory proteins may play a role in the pathophysiology of cerebral arteriovenous malformations and their response to radiosurgery. The aim of this study was to compare the expression of inflammatory molecules in arteriovenous malformations (AVMs) with that in normal cerebral vessels. Fresh-frozen surgical specimens from 15 AVMs and three control specimens were studied. The expression of P-and E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule (PECAM-1) and von Willebrand factor were examined using immunohistochemistry. AVMs had significant upregulation of E-selectin. VCAM-1 and ICAM-1 upregulation was also observed in AVMs. Pre-operative embolization was associated with increased expression of E-selectin and VCAM-1. This study has provided further evidence that the endothelium of AVMs has different molecular properties than the endothelium of normal cerebral vasculature. Inflammatory molecules may be biologically relevant in the response of vascular malformations to radiosurgery and embolization.