Implication of the hypoxia response element of the vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development

Vinores, Stanley A.; Xiao, Wei; Aslam, Sadia; Shen, Jikui; Oshima, Yuji; Nambu, Hiroyuki; Liu, Hansheng; Carmeliet, Peter; Campochiaro, Peter A.

doi:10.1002/jcp.20525

Cited by 90 publications

(65 citation statements)

References 87 publications

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“…Consistent with this finding, a recent study showed that hypoxia could markedly increase the expression of HIF-1a in RPE cells (Wang et al, 2005). These data suggest that if the UPP function is compromised, RPE cells behave as if they were under hypoxic conditions, expressing and secreting high levels of pro-angiogenic factors (Blaauwgeers et al, 1999;Mousa et al, 1999;Schlingemann, 2004;Vinores et al, 2006).…”

Section: Discussionsupporting

confidence: 61%

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

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As in many other types of cells, retinal pigment epithelial (RPE) cells have an active ubiquitineproteasome pathway (UPP). However, the function of the UPP in RPE remains to be elucidated. The objective of this study is to determine the role of the UPP in controlling the levels and activities of transcription factors hypoxia-inducible factor (HIF) and NF-kB. We inhibited the UPP with proteasome-specific inhibitors and determined the activation of HIF and NF-kB as well as the expression and secretion of pro-angiogenic factors. HIF-1a was not detectable in ARPE-19 cells under normal culture conditions. However, when proteasome activity was inhibited, HIF-1a accumulated in RPE in a time-dependent manner. Consistent with accumulation of HIF-1a in the cells, levels of mRNA for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in RPE were up to 7-fold higher upon inhibition of the proteasome. Proteasome inhibition was also associated with a 2-fold increase in levels of mRNA for angiopoietin-1 (Ang-1). ARPE-19 cells secrete significant levels of VEGF under normal culture conditions. Inhibition of proteasome activity increased the secretion of VEGF by 2-fold. In contrast to the increase in HIF activity, NF-kB activation was reduced by proteasome inhibition. In addition, the expression and secretion of monocyte chemoattractant protein-1 (MCP-1) by RPE were substantially attenuated by the inhibition of proteasome activity. These data demonstrate that the UPP plays an important role in modulating the activities of HIF and NF-kB in the RPE. Consequences of an impairment of the UPP include accumulation of HIF-1a and diminished NF-kB activation, which lead to enhanced expression and secretion of pro-angiogenic factors and attenuated expression of MCP-1. Taken together, these data predict that the impairment of the UPP could lead to the development of AMD-related phenotypes.

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Section: Discussionsupporting

confidence: 61%

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

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“…50 In spite of similarities with CNV in human age-related macular degeneration, the laser model may not be appropriate for studies of mechanisms of initiation of CNV as there is extensive damage to the retinal issue and Bruch's membrane with the laser treatment. However, Vinores et al 51 have shown that the hypoxia response element of the VEGF promoter is critical for the development of CNV after laser-induced rupture of Bruch's membrane. This may mean that laserinduced closure of choroidal vessels causes ischemia of pDNA-loaded nanoparticles inhibit CNV C Zhang et al the outer retina resulting in VEGF upregulation, which combined with the disruption of Bruch's membrane causes CNV.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

Zhang

et al. 2009

Gene Ther

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The aim of this study was to evaluate the possibility of poly (D, L-lactide-co-glycolide) nanoparticle (NPs) as a gene vector for functional plasmid DNA (pDNA) and to investigate its inhibitory efficacy on experimental choroidal neovascularization (CNV). We developed intravitreal administered, hypoxia-inducible factor 1a (HIF-1a) short hairpin RNA and green fluorescent protein (GFP) co-expressed pDNA-loaded NPs (pshHIF-1a NPs). CNV was induced by laser photocoagulation in 112 rats. The rats were then randomly assigned to be injected intravitreally with phosphate-buffered saline (PBS), blank NPs, naked pDNA, control pDNA NPs and pshHIF-1a NPs, respectively, and non-injection group was set as the control. Immunofluorescence staining, fluorescein fundus angiography and histologic analysis were performed to evaluate the inhibitory efficacy on CNV. The results showed that the expression of GFP preferentially localized in the retinal pigment epithelium cell layer and lasted for 4 weeks. The fluorescein leakage areas of CNV were significantly larger in the PBS, blank NPs, control pDNA NPs, non-injection group and naked pDNA group than in pshHIF-1a NPs group (Po0.01). The mean thickness of the CNV lesions in the intravitreally pshHIF1a NPs-treated group was significantly smaller than other groups (Po0.01). No signs of functional or ultrastructural destruction in retina were detected. Therefore, pshHIF-1a NPs may act as a novel therapeutic option to transfer specific pDNA and inhibit the formation of experimental CNV.

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“…N4 angiogenic activity was evaluated by using the mouse model of laser-induced choroidal neovascularization (18). In the control eye, N4 was slightly expressed (Fig.…”

Section: N4mentioning

confidence: 99%

Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B

Lejmi

Leconte

Pédron-Mazoyer

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

134

162

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Netrins are secreted molecules with roles in axon guidance and angiogenesis. We identified Netrin-4 as a gene specifically overexpressed in VEGF-stimulated endothelial cells (EC) in vitro as well as in vivo. Knockdown of Netrin-4 expression in EC increased their ability to form tubular structures on Matrigel. To identify which receptor is involved, we showed by quantitative RT-PCR that EC express three of the six Netrin-1 cognate receptors: neogenin, Unc5B, and Unc5C. In contrast to Netrin-1, Netrin-4 bound only to neogenin but not to Unc5B or Unc5C receptors. Neutralization of Netrin-4 binding to neogenin by blocking antibodies abolished the chemotactic effect of Netrin-4. Furthermore, the silencing of either neogenin or Unc5B abolished Netrin-4 inhibitory effect on EC migration, suggesting that both receptors are essential for its function in vitro. Coimmunoprecipitation experiments demonstrated that Netrin-4 increased the association between Unc5B and neogenin on VEGF-or FGF-2-stimulated EC. Finally, we showed that Netrin-4 significantly reduced pathological angiogenesis in Matrigel and laser-induced choroidal neovascularization models. Interestingly, Netrin-4, neogenin, and Unc5B receptor expression was up-regulated in choroidal neovessel EC after laser injury. Moreover, Netrin-4 overexpression delayed tumor angiogenesis in a model of s.c. xenograft. We propose that Netrin-4 acts as an antiangiogenic factor through binding to neogenin and recruitment of Unc5B.

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Implication of the hypoxia response element of the vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development

Cited by 90 publications

References 87 publications

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B

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