Interleukin‐6 involvement in brain arteriovenous malformations

Chen, Yongmei; Pawlikowska, Ludmila; Yao, John; Shen, Fanxia; Zhai, Wenwu; Achrol, Achal S.; Lawton, Michael T.; Kwok, Pui‐Yan; Yang, Guo‐Yuan; Young, William L.

doi:10.1002/ana.20697

Cited by 122 publications

(109 citation statements)

References 37 publications

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“…We have found that the transduced protein is expressed at 3 days, reaching maximal levels at 3 weeks after viral injection (Fan et al, 2008;Shen et al, 2006a;Zhu et al, 2008). AAV gene transfer did not cause neuronal death and inflammation at 6 days after transduction (Shen et al, 2006b, Shen, 2006. Despite the sustained increase in vascular density, we did not observe any evidence of abnormal vessel morphology for up to 6 weeks following administration of Del-1, using previously published criteria .…”

Section: Del-1 Gene Transfer Induced Cerebral Angiogenesissupporting

confidence: 55%

Del-1 gene transfer induces cerebral angiogenesis in mice

et al. 2008

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Developmental endothelial locus-1 (Del-1) is a novel angiomatrix protein that has been shown to stimulate a potent angiogenic response and promote functional recovery in hind limb and cardiac ischemia in animal models; however, its impact on cerebral angiogenesis is unknown. In this study, we investigated whether Del-1 overexpression via gene transfer induces cerebral angiogenesis in a murine model, and examined Del-1 expression after ischemic stroke. Cerebral Del1-1 overexpression was achieved with AAV (adeno-associated virus) transduction system via stereotactic injection. Control mice were injected with AAV-lacZ. Del-1gene transduction led to a significant induction of cerebral angiogenesis compared to AAV-lacZ treatment at 4 weeks after gene transfer (Del-1: 97±7 vs lacZ: 64±28, vessels/field, p<0.05). Mice transduced with AAV-Del-1 showed significantly elevated vascular densities for up to 6 weeks after gene delivery. In addition, double immunofluorescent staining showed co-localization of endothelial cell marker CD31 with BrdU (specific marker for proliferating cells), indicating that Del-1 promoted endogenous endothelial cell proliferation and angiogenesis. Our immunohistochemcial staining also showed that Del-1 expression was markedly upregulated in the peri-infarct area at 3 days after permanent focal cerebral ischemia compared to the sham-operated non-ischemic control. Our data suggest that Del-1 may participate in modulating cerebral angiogenesis, and that gene transfer of Del-1 may provide a novel and potent means for stimulating cerebral angiogenesis.

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Section: Del-1 Gene Transfer Induced Cerebral Angiogenesissupporting

confidence: 55%

Del-1 gene transfer induces cerebral angiogenesis in mice

et al. 2008

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“…When IL-6 is expressed in large amounts, there is a significant increase in the mRNA levels of IL-1β, TNF-α, and IL-8 in human AVM tissues. 21 Through the upregulation of these cytokines, IL-6 indirectly stimulates leukocyte recruitment, endothelial activation, and vascular smooth muscle cell (SMC) proliferation (Table 2). Leukocyte recruitment occurs when the cellular adhesion molecules (CAMs) of ECs bind circulating leukocytes and affix them to the site of inflammation.…”

Section: Effect Of Increased Proinflammatory Cytokines On Avms: a Cenmentioning

confidence: 99%

“…Leukocyte recruitment IL-6, TNF-α, and IL-1β 21 Overexpression of E-selectin, ICAM-1, and VCAM-1 22 Angiogenesis IL-6, VEGF, HIF-1, NF-κB, IL-1β, and IL-8 21,59,64 EC proliferation [21][22][23]43 EC migration 22,43 CAM expression 22 Decreased EC apoptosis 43 …”

Section: Inflammatory Mediators Involved Inflammatory Pathwaymentioning

confidence: 99%

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Mouchtouris

Jabbour

Starke

et al. 2014

J Cereb Blood Flow Metab

124

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Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

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“…We found that the GG genotype of the interleukin-6 (IL-6 -174G>C) promoter polymorphism was associated with clinical presentation of ICH [45]. The high risk IL-6 -174 GG genotype was also associated with the highest IL-6 mRNA and protein levels in AVM tissue [13]. We have not yet identified any associations of sporadic AVM with polymorphisms in genes coding for important angiogenesis-related proteins, such as VEGF, TIE-2 or the angiopoietins.…”

Section: Candidate Gene Studies In Avm Patientsmentioning

confidence: 89%

“…MMP-9 expression in particular appears to be orders of magnitude higher in AVM than control tissue [12,27], with levels of naturally occurring MMP inhibitors, TIMP-1 and TIMP-3, also higher, but to a lesser degree. Additional inflammatory markers that are overexpressed include myeloperoxidase (MPO) and IL-6, both of which are highly correlated with MMP-9 [12,13]. MMP-9 expression is correlated with the lipocalin-MMP-9 complex, suggesting neutrophils as a major source.…”

Section: Characterization Of Lesional Tissuementioning

confidence: 99%

Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

Kim

Marchuk

Pawlikowska

et al.

Acta Neurochirurgica Supplementum

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SUMMARYBrain arteriovenous malformations (AVM) cause intracranial hemorrhage (ICH), especially in young adults. Molecular characterization of lesional tissue provides evidence for involvement of both angiogenic and inflammatory pathways, but the pathogenesis remain obscure and medical therapy is lacking. Abnormal expression patterns have been observed for proteins related to angiogenesis (e.g., VEGF, Angiopoietin-2, MMP-9), and inflammation (e.g., IL-6 and MPO). Macrophage and neutrophil invasion has also been observed in the absence of prior ICH. Candidate gene association studies have identified a number of germline variants associated with clinical ICH course and AVM susceptibility. A single nucleotide polymorphism (SNP) in ALK-1 is associated with AVM susceptibility, and SNPs in IL-6, TNF-α and APOE are associated with AVM rupture. These observations suggest that even without a complete understanding of the determinants of AVM development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Further, biomarkers can now be established for assessing ICH risk. Finally, these data will generate hypotheses that can be tested mechanistically in model systems, including surrogate phenotypes, such as vascular dysplasia and/or models recapitulating the clinical syndrome of recurrent spontaneous ICH. Keywords angiogenesis; inflammation; vascular malformationsBrain arteriovenous malformations (AVM) represent a relatively infrequent but important source of neurological morbidity in relatively young adults [4]. Brain AVMs have a population prevalence of 10-18 per 100,000 adults [3,7], and a new detection rate of ~1.3 per 100,000 person-years [58]. The basic morphology is of a vascular mass, called the nidus, that directly shunts blood between the arterial and venous circulations without a true capillary bed. There is usually high flow through the feeding arteries, nidus and draining veins. The nidus is a

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Interleukin‐6 involvement in brain arteriovenous malformations

Cited by 122 publications

References 37 publications

Del-1 gene transfer induces cerebral angiogenesis in mice

Del-1 gene transfer induces cerebral angiogenesis in mice

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Genetic considerations relevant to intracranial hemorrhage and brain arteriovenous malformations

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