Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia

Håkansson, Gisela; Gesslein, Bodil; Gustafsson, Lotta; Englund-Johansson, Ulrica; Malmsjö, Malin

doi:10.1007/s12177-010-9050-6

Cited by 14 publications

(12 citation statements)

References 25 publications

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“…Secondly, LPS treatment triggered increased apoptotic cell loss, transient in the GCL and INL, but sustained in the ONL. This might indicate that photoreceptors are more vulnerable to inflammation caused by LPS [ 32 , 33 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

Inflamed In Vitro Retina: Cytotoxic Neuroinflammation and Galectin-3 Expression

et al. 2016

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BackgroundDisease progression in retinal neurodegeneration is strongly correlated to immune cell activation, which may have either a neuroprotective or neurotoxic effect. Increased knowledge about the immune response profile and retinal neurodegeneration may lead to candidate targets for treatments. Therefore, we have used the explanted retina as a model to explore the immune response and expression of the immune modulator galectin-3 (Gal-3), induced by the cultivation per se and after additional immune stimulation with lipopolysaccharide (LPS), and how this correlates with retinal neurotoxicity.MethodsPost-natal mouse retinas were cultured in a defined medium. One group was stimulated with LPS (100 ng/ml, 24 h). Retinal architecture, apoptotic cell death, and micro- and macroglial activity were studied at the time of cultivation (0 days in vitro (DIV)) and at 3, 4 and 7 DIV using morphological staining, biochemical- and immunohistochemical techniques.ResultsOur results show that sustained activation of macro- and microglia, characterized by no detectable cytokine release and limited expression of Gal-3, is not further inducing apoptosis additional to the axotomy-induced apoptosis in innermost nuclear layer. An elevated immune response was detected after LPS stimulation, as demonstrated primarily by release of immune mediators (i.e. interleukin 2 (IL-2), IL-6, KC/GRO (also known as CLCX1) and tumour necrosis factor-α (TNF-α)), increased numbers of microglia displaying morphologies of late activation stages as well as Gal-3 expression. This was accompanied with increased apoptosis in the two additional nuclear layers, and damage to retinal gross architecture.ConclusionWe demonstrate that an immune response characterized by sustained and increased release of cytokines, along with an increase in Gal-3 expression, is accompanied by significant increased neurotoxicity in the explanted retina. Further investigations using the current setting may lead to increased understanding on the mechanisms involved in neuronal loss in retinal neurodegenerations.

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Section: Resultsmentioning

confidence: 99%

Inflamed In Vitro Retina: Cytotoxic Neuroinflammation and Galectin-3 Expression

et al. 2016

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“…AdMSCs have also been found to enhance stemness and to secrete various therapeutic factors while decreasing lineage commitment under hypoxic culture conditions . Hypoxia‐inducible transcription factors (HIFs) have been identified as pivotal regulators of cell adaption to HPX and correlated with cell survival because of induction of angiogenic factors such as VEGF, HGF, and basic FGF, and regulation of stem cell‐related factors such as Oct4 and Notch . Overexpression of HIF1α in MSCs showed increased paracrine activity and regenerative potential .…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Activated Adipose Mesenchymal Stem Cells Prevents Irradiation-Induced Salivary Hypofunction by Enhanced Paracrine Effect Through Fibroblast Growth Factor 10

et al. 2018

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To explore the effects and mechanisms of paracrine factors secreted from human adipose mesenchymal stem cell (hAdMSCs) that are activated by hypoxia on radioprotection against irradiation-induced salivary hypofunction in subjects undergoing radiotherapy for head and neck cancers. An organotypic spheroid coculture model to mimic irradiation (IR)-induced salivary hypofunction was set up for in vitro experiments. Human parotid gland epithelial cells were organized to form three-dimensional (3D) acinus-like spheroids on growth factor reduced -Matrigel. Cellular, structural, and functional damage following IR were examined after cells were cocultured with hAdMSCs preconditioned with either normoxia (hAdMSC ) or hypoxia (hAdMSC ). A key paracrine factor secreted by hAdMSCs was identified by high-throughput microarray-based enzyme-linked immunosorbent assay. Molecular mechanisms and signaling pathways on radioprotection were explored. Therapeutic effects of hAdMSCs were evaluated after in vivo transplant into mice with IR-induced salivary hypofunction. In our 3D coculture experiment, hAdMSCs significantly enhanced radioresistance of spheroidal human parotid epithelial cells, and led to greater preservation of salivary epithelial integrity and acinar secretory function relative to hAdMSCs . Coculture with hAdMSCs promoted FGFR expression and suppressed FGFR diminished antiapoptotic activity of hAdMSCs . Among FGFR-binding secreted factors, we found that fibroblast growth factor 10 (FGF10) contributed to therapeutic effects of hAdMSCs by enhancing antiapoptotic effect, which was dependent on FGFR-PI3K signaling. An in vivo transplant of hAdMSCs into irradiated salivary glands of mice reversed IR-induced salivary hypofunction where hAdMSC-released FGF10 contributed to tissue remodeling. Our results suggest that hAdMSCs protect salivary glands from IR-induced apoptosis and preserve acinar structure and functions by activation of FGFR-PI3K signaling via actions of hAdMSC-secreted factors, including FGF10. Stem Cells 2018;36:1020-1032.

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“…It is thus important to discover novel approaches that are able to stimulate self-protective mechanisms within the eye and that help to avoid detrimental neovascularization. Elevated concentrations of the hypoxia-inducible factor-1α (HIF-1α) have been demonstrated after retinal ischemia [ 6 ]. HIF-1α interacts with hypoxia dependence components of various hypoxia related genes and up-regulates the level of vascular endothelium growth factor (VEGF) [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Xue-fu-Zhu-Yu decoction protects rats against retinal ischemia by downregulation of HIF-1α and VEGF via inhibition of RBP2 and PKM2

Tan

Geng

Liu

et al. 2017

BMC Complement Altern Med

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BackgroundRetinal ischemia-related eye diseases result in visual dysfunction. This study investigates the protective effects and mechanisms of Xue-Fu-Zhu-Yu decoction (XFZYD) with respect to retinal ischemia.MethodsRetinal ischemia (I) was induced in Wistar rats by a high intraocular pressure (HIOP) of 120 mmHg for 1 h, which was followed by reperfusion of the ischemic eye; the fellow untreated eye acted as a control. Electroretinogram (ERG), biochemistry and histopathology investigations were performed.ResultsSignificant ischemic changes occurred after ischemia including decreased ERG b-wave ratios, less numerous retinal ganglion cells (RGCs), reduced inner retinal thickness, fewer choline acetyltransferase (ChAT) labeled amacrine cell bodies, increased glial fibrillary acidic protein (GFAP) immunoreactivity and increased vimentin Müller immunolabeling. These were accompanied by significant increases in the mRNA/protein concentrations of vascular endothelium growth factor, hypoxia-inducible factor-1α, pyruvate kinase M2 and retinoblastoma-binding protein 2. The ischemic changes were concentration-dependently and significantly altered when XFZYD was given for seven consecutive days before or after retina ischemia, compared to vehicle. These alterations included enhanced ERG b-wave amplitudes, more numerous RGCs, enhanced inner retinal thickness, a greater number of ChAT immunolabeled amacrine cell bodies and decreased GFAP/vimentin immunoreactivity. Furthermore, decreased mRNA levels of VEGF, HIF-1α, PKM2, and RBP2 were also found. Reduced protein concentrations of VEGF, HIF-1α, PKM2, and RBP2 were also demonstrated. Furthermore, there was an inhibition of the ischemia-associated increased ratios (target protein/β-actin) in the protein levels of VEGF, HIF-1α, PKM2, and RBP2, which were induced by Shikonin, JIB-04 or Avastin.ConclusionXFZYD would seem to protect against well-known retinal ischemic changes via a synergistic inhibition of RBP2 and PKM2, as well as down-regulation of HIF-1α and a reduction in VEGF secretion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1857-2) contains supplementary material, which is available to authorized users.

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Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia

Cited by 14 publications

References 25 publications

Inflamed In Vitro Retina: Cytotoxic Neuroinflammation and Galectin-3 Expression

Inflamed In Vitro Retina: Cytotoxic Neuroinflammation and Galectin-3 Expression

Hypoxia-Activated Adipose Mesenchymal Stem Cells Prevents Irradiation-Induced Salivary Hypofunction by Enhanced Paracrine Effect Through Fibroblast Growth Factor 10

Xue-fu-Zhu-Yu decoction protects rats against retinal ischemia by downregulation of HIF-1α and VEGF via inhibition of RBP2 and PKM2

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