The Role of eNOS in Vascular Permeability in ENU-Induced Gliomas

Bulnes, Susana; Argandoña, Enrike; Bengoetxea, Harkaitz; Leis, Olga; Ortuzar, Naiara; Lafuente, José Vicente

doi:10.1007/978-3-211-98811-4_52

Cited by 21 publications

(14 citation statements)

References 19 publications

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“…It has been suggested that increased permeability may be related to any combination of the following factors: breakdown of the astrocyte-vascular endothelial interaction and loss of vascular pericyte coverage [52], increased eNOS synthesis secondary to VEGF secretion from cancer cells [53], the presence of inflammatory cytokines such as TGFβ [54], the process of angiogenesis [55], and the dysregulation of tight junction proteins in the BTB [56]. Changes in vascular permeability may actually be a representation of all factors at one given time in the local tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

Adkins

Mohammad

Terrell-Hall

et al. 2016

Clin Exp Metastasis

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The blood brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers 14C-aminoisobutyric acid (AIB) and Texas Red conjugated dextran (TRD) prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.

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Section: Discussionmentioning

confidence: 99%

Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

Adkins

Mohammad

Terrell-Hall

et al. 2016

Clin Exp Metastasis

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“…For example, cigarette smoke has been shown to lead to cerebrovascular vasodilation through sympathetic activation. Nicotine activates nicotine receptors, which leads to the acetylcoline-dependent release of NO from the vascular endothelium [47,48] through activation of endothelial nitric oxide synthase (eNOS) [49]. NO is one of the major endothelium-derived relaxing factors, which plays an active role in regulating microvascular tone and the cerebral blood flow under normal and pathological conditions [50].…”

Section: Pathophysiology Of Bbb Endothelial Cellsmentioning

confidence: 99%

Pathophysiological Impact of Cigarette Smoke Exposure on the Cerebrovascular System with a Focus on the Blood-brain Barrier: Expanding the Awareness of Smoking Toxicity in an Underappreciated Area

Mazzone

Tierney

Hossain

et al. 2010

IJERPH

157

111

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Recent evidence has indicated that active and passive cigarette smoking are associated, in a dose-dependent manner, with dysfunction of normal endothelial physiology. Tobacco smoke (TS) may predispose individuals to atherogenic and thrombotic problems, significantly increasing the risk for ischemic manifestations such as acute coronary syndrome and stroke. Despite the strong evidence for an association between smoking and vascular impairment, the impact of TS exposure on the blood-brain barrier (BBB) has only been marginally addressed. This is a major problem given that the BBB is crucial in the maintenance of brain homeostasis. Recent data have also shown that chronic smokers have a higher incidence of small vessel ischemic disease (SVID), a pathological condition characterized by leaky brain microvessels and loss of BBB integrity. In the brain OPEN ACCESS Int. J. Environ. Res. Public Health 2010, 7 4112TS increases the risk of silent cerebral infarction (SCI) and stroke owing to the pro-coagulant and atherogenic effects of smoking. In this article we provide a detailed review and analysis of current knowledge of the pathophysiology of tobacco smoke toxicity at the cerebrovascular levels. We also discuss the potential toxicity of recently marketed "potential-reduced exposure products".

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“…NO activity has been extensively studied in tumor biology (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). It appears to be involved in all phases of carcinogenesis (12).…”

Section: Effects Of Nitric Oxide Synthase Deficiency On a Disintegrinmentioning

confidence: 99%

“…eNOS-derived NO has been shown to enhance angiogenesis in gliomas (14). Low grade gliomas demonstrate constitutive expression of eNOS in vessel endothelial cells and astrocytes, whereas malignant gliomas demonstrate overexpression of eNOS in aberrant vessels (15). Furthermore, studies have demonstrated that eNOS-deficient (eNOS -/-) mice may be resistant to chemical carcinogenesis (16) and platelet-derived growth factor-induced gliomagenesis (17).…”

Section: Effects Of Nitric Oxide Synthase Deficiency On a Disintegrinmentioning

confidence: 99%

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples

Lendeckel¹,

Wolke²,

Bernstein

et al. 2015

Molecular Medicine Reports

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Abstract.A d isi nt eg r i n a nd met a l loprot ei nase domain-containing protein 12 (ADAM12) belongs to the ADAM family of transmembrane proteins. Via proteolysis, cell adhesion, cell-cell fusion, cell-matrix interaction and membrane protein shedding, ADAM proteins are involved in normal brain development, and also in cancer genesis and progression, and in inflammation. Therefore, neurobiological research focusing on this protein is increasing. Nitric oxide (NO), which is endogenously produced by NO synthases (NOS), is associated with glial tumors. However, knock-out of NOS produces only limited antitumor effects. The present study analyzed the expression of ADAM12 in the cortex and hippocampus of C57/BL6 wild-type mice, and endothelial NOS-, neuronal NOS-(nNOS) or inducible NOS (iNOS)-deficient ( -/-) mice, at different stages of development. Expression of ADAM12 was quantified using immunoblot analysis of cortical and hippocampal tissue samples from fetal, neonatal (5 days postnatal), adult (12 weeks old) or >1 year old mice. Using reverse transcription-quantitative polymerase chain reaction, ADAM12 expression was analyzed in cultured N9, OLN93, C6 and PC12 cells, representing the four main cell types in the brain, following NOS inhibition. ADAM12 expression was low in all mouse genotypes and regions of the brain, and in fetal and neonatal mice, an increase in expression was observed with increasing age. The highest levels of expression were observed in the cortex of adult mice, iNOS -/-mice of >1 year and wild-type mice, and in the hippocampus of adult and iNOS -/-mice of >1 year. By contrast, ADAM12 expression was lowest in adult nNOS -/-mice. Inhibition of NOS using N ω -Nitro-L-arginine methyl ester hydrochloride, induced ADAM12 mRNA expression in N9 and PC12 cell lines. Inhibition of NOS using L-N 6 -(1-Iminoethyl)lysine dihydrochloride, induced ADAM12 mRNA expression in N9 and C6 cell lines. No change in ADAM12 expression was observed in OLN93 cells following NOS inhibition. ADAM12 expression in mouse hippocampus and cortex samples demonstrated considerable variation during development, with a marked increase observed in adult and >1 year old mice, compared with that in fetal and neonatal mice. IntroductionNitric oxide (NO) is an important signaling molecule found in animals, including humans. Reduced NO production is associated with important cardiovascular risk factors, such as hyperlipidemia (1,2), diabetes, hypertension, smoking, atherosclerosis and aging (3). The bioavailability of NO in cells and tissues decreases with age. This may be a result of a decrease in the expression of the constitutive isoforms [endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS)], with age (4). Inducible NOS (iNOS)-mediated NO formation has been shown to affect longevity. In mice, iNOS overexpression may lead to increased mortality, which is associated with cardiac hypertrophy and sudden cardiac death as a result of bradyarrhythmias (5). iNOS expression is typically not observed in the brains of young (1-3...

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The Role of eNOS in Vascular Permeability in ENU-Induced Gliomas

Cited by 21 publications

References 19 publications

Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

Pathophysiological Impact of Cigarette Smoke Exposure on the Cerebrovascular System with a Focus on the Blood-brain Barrier: Expanding the Awareness of Smoking Toxicity in an Underappreciated Area

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples

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