Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

Hu, Jiong; Popp, Rüdiger; Frömel, Timo; Ehling, Manuel; Awwad, Khader; Adams, Ralf H.; Hammes, Hans‐Peter; Fleming, Ingrid

doi:10.1084/jem.20131494

Cited by 69 publications

(77 citation statements)

References 67 publications

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“…Moreover, the stabilized EDP also inhibited Met-1 breast tumor growth (a highly aggressive triple-negative breast cancer model) in mice by ~70% 29 . Our findings demonstrate potent effects of EDPs on tumor angiogenesis, however, two recent studies showed that EDPs did not impact angiogenesis in retinal angiogenesis models 96, 97 . More studies are needed to characterize the effects and mechanisms of ω-3-series epoxides and diols on angiogenesis in different disease models as it is likely that the effects of these LMs may be disease- and tissue-specific.…”

Section: Cyp-derived ω-3 Lms In Angiogenesis Inflammation and Cancercontrasting

confidence: 55%

ω-3 Polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer

Wang

Zhu

Lyu

et al. 2014

Prostaglandins & Other Lipid Mediators

120

102

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Epidemiological and pre-clinical studies support the anti-tumor effects of ω-3 PUFAs; however, the results from human trials are mixed, making it difficult to provide dietary guidelines or recommendations of ω-3 PUFAs for disease prevention or treatment. Understanding the molecular mechanisms by which ω-3 PUFAs inhibit cancer could lead to better nutritional paradigms and human trials to clarify their health effects. The ω-3 PUFAs exert their biological activities mainly through the formation of bioactive lipid metabolites. Here we discuss the biology of cyclooxygenase, lipoxygenase and cytochrome P450 enzymes-derived ω-3-series lipid metabolites on angiogenesis, inflammation and cancer.

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Section: Cyp-derived ω-3 Lms In Angiogenesis Inflammation and Cancercontrasting

confidence: 55%

ω-3 Polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer

Wang

Zhu

Lyu

et al. 2014

Prostaglandins & Other Lipid Mediators

120

102

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“…The adenovirus encoding the human sEH under the control of a CMV promoter was generated as previously reported 7 . To generate the sEH mutant deficient in epoxide hydrolase activity (sEH ΔEH ) the tyrosine residues Tyr383 and Tyr466 were mutated to phenylalanine in the pAd-shuttle sEH vector using the following primers (Biospring GmbH, Frankfurt, Germany: Y381F: 5′-gccaacccagtatttgatttccagctctacttccaagaaccagg-3′, Y465F: 5′-gtcctctaaactggttccgaaacatggaaaggaactggaagtgg-3′).…”

Section: Methodsmentioning

confidence: 99%

“…1a–d). The sEH was expressed in the adult murine retinas from wild-type and Ins2 Akita mice and largely colocalized with aquaporin 4 and glutamine synthetase, indicating expression in Müller glia cells 7 (Fig. 1a, Extended Data Fig.…”

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confidence: 98%

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Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy

Dziumbla

Lin

et al. 2017

Nature

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118

114

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Diabetic retinopathy is an important cause of blindness in the adult population1,2 and is characterized by a progressive loss of vascular cells and slow dissolution of inter-vascular junctions resulting in vascular leak and retinal edema3. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization4,5. Here we identify the soluble epoxide hydrolase (sEH) as a key enzyme that initiates the pericyte “drop off” and loss of endothelial barrier function by generating a diol from docosahexaenoic acid (DHA) i.e. 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). The expression of the sEH and the accumulation of 19,20-DHDP were elevated in diabetic murine and human retinas as well as in human vitreous. Mechanistically, the diol targeted the cell membrane to alter the localisation of cholesterol-binding proteins, and interfered with the association of presenilin 1 (PS1) with N-cadherin and VE-cadherin to compromise pericyte-endothelial cell as well as inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Overexpression of the sEH in the retinal Müller glial cells of non-diabetic mice, on the other hand, resulted in vessel abnormalities similar to those seen in diabetic animals with retinopathy. Thus, increased expression of the sEH is a determinant event in the pathogenesis of diabetic retinopathy and sEH inhibition can prevent the progression of the disease.

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“…Müller cells were isolated from 8-10-day-old NDPK-B deficient and wild type (WT) mice as previously described [26,27]. The cells were cultured at 37 • C, 5% CO 2 in a humidified incubator in DMEM containing 10% FCS, 200 mM Glutamine, which was replenished every 3-4 days.…”

Section: Cell Culture and High Glucose Stimulationmentioning

confidence: 99%

Mediation of FoxO1 in Activated Neuroglia Deficient for Nucleoside Diphosphate Kinase B during Vascular Degeneration

et al. 2018

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Abstract:The pathogenesis of diabetic retinopathy is closely associated with the breakdown of the neurovascular unit including the glial cells. Deficiency of nucleoside diphosphate kinase B (NDPK-B) results in retinal vasoregression mimicking diabetic retinopathy. Increased retinal expression of Angiopoietin-2 (Ang-2) initiates vasoregression. In this study, Müller cell activation, glial Ang-2 expression, and the underlying mechanisms were investigated in streptozotocin-induced diabetic NDPK-B deficient (KO) retinas and Müller cells isolated from the NDPK-B KO retinas. Müller cells were activated and Ang-2 expression was predominantly increased in Müller cells in normoglycemic NDPK-B KO retinas, similar to diabetic wild type (WT) retinas. Diabetes induction in the NDPK-B KO mice did not further increase its activation. Additionally, cultured NDPK-B KO Müller cells were more activated and showed higher Ang-2 expression than WT cells. Müller cell activation and Ang-2 elevation were observed upon high glucose treatment in WT, but not in NDPK-B KO cells. Moreover, increased levels of the transcription factor forkhead box protein O1 (FoxO1) were detected in non-diabetic NDPK-B KO Müller cells. The siRNA-mediated knockdown of FoxO1 in NDPK-B deficient cells interfered with Ang-2 upregulation. These data suggest that FoxO1 mediates Ang-2 upregulation induced by NDPK-B deficiency in the Müller cells and thus contributes to the onset of retinal vascular degeneration.

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Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

Abstract: DHA diols produced by Müller cells suppress Notch activation in endothelial cells, thereby promoting retinal angiogenesis.

Cited by 69 publications

References 67 publications

ω-3 Polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer

ω-3 Polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer

Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy

Mediation of FoxO1 in Activated Neuroglia Deficient for Nucleoside Diphosphate Kinase B during Vascular Degeneration

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