Accelerated oxygen-induced retinopathy is a reliable model of ischemia-induced retinal neovascularization

Villacampa, Pilar; Menger, Katja E.; Abelleira, Laura; Ribeiro, Joana; Durán, Yanaí; Smith, Alexander J.; Ali, Robin R.; Luhmann, Ulrich F O; Bainbridge, James

doi:10.1371/journal.pone.0179759

Cited by 14 publications

(12 citation statements)

References 12 publications

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“…Notably, the ischemia‐induced retinal neovascularization in this model is not caused by HG. However, retinal ischemia, pre‐retinal neovascularization and retinal gliosis, are all reproducible characteristic of DR applicable to the OIR mouse model . In fact, we demonstrated that ASC SH‐NOTCH2, retained the therapeutic capacities without physically interacting with inner layers of the retina microvasculature.…”

Section: Discussionmentioning

confidence: 73%

The Pericytic Phenotype of Adipose Tissue-Derived Stromal Cells Is Promoted by NOTCH2

et al. 2017

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Long-term diabetes leads to macrovascular and microvascular complication. In diabetic retinopathy (DR), persistent hyperglycemia causes permanent loss of retinal pericytes and aberrant proliferation of microvascular endothelial cells (ECs). Adipose tissue-derived stromal cells (ASCs) may serve to functionally replace retinal pericytes and normalize retinal microvasculature during disease progression. We hypothesized that Notch signaling in ASC underlies regulation and stabilization of dysfunctional retinal microvascular networks such as in DR. ASC prominently and constitutively expressed NOTCH2. Genetic knockdown of NOTCH2 in ASC (SH-NOTCH2) disturbed the formation of vascular networks of human umbilical cord vein endothelial cells both on monolayers of ASC and in organotypical three-dimensional cocultures with ASC. On ASC SH-NOTCH2, cell surface platelet-derived growth factor receptor beta was downregulated which disrupted their migration toward the chemoattractant platelet-derived growth factor beta subunits (PDGF-BB) as well as to conditioned media from EC and bovine retinal EC. This chemoattractant is secreted by pro-angiogenic EC in newly formed microvascular networks to attract pericytes. Intravitreal injected ASC SH-NOTCH2 in oxygen-induced retinopathy mouse eyes did not engraft in the preexisting retinal microvasculature. However, the in vivo pro-angiogenic capacity of ASC SH-NOTCH2 did not differ from controls. In this respect, multifocal electroretinography displayed similar b-wave amplitudes in the avascular zones when either wild type ASC or SH-NOTCH2 ASC were injected. In conclusion, our results indicate that NOTCH2 is essential to support in vitro vasculogenesis via juxtacrine interactions. In contrast, ongoing in vivo angiogenesis is influenced by paracrine signaling of ASC, irrespective of Notch signaling. STEM CELLS 2018;36:240-251 SIGNIFICANCE STATEMENTIn this study, NOTCH2 is identified as a novel regulator of pericytic phenotype of human adipose tissue-derived stromal cells (ASCs). Results show that NOTCH2 modulates (a) ASC migration to the retinal microenvironment and (b) endothelial cells assembly in a vessel network formation in vitro. At the molecular level, NOTCH2 promotes the ASC pericytic phenotype through plateletderived growth factor receptor beta expression and sensitivity to chemoattractant.

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Section: Discussionmentioning

confidence: 73%

The Pericytic Phenotype of Adipose Tissue-Derived Stromal Cells Is Promoted by NOTCH2

et al. 2017

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“…In this model, the immature retinal vasculature of pups exposed to transient hyperoxia regresses and fails to sustain retinal oxygen consumption on return to normoxia, causing Vegfa upregulation and thereby both beneficial retinal revascularization and pathological neovascular tufts (22,23). To induce OIR, we exposed wild-type pups to either 75% oxygen for 5 days (21) or 85% oxygen for 3 days (24). We analyzed Vegfa isoform expression in the retina on days 1 and 5 after return to normoxia, i.e., shortly after ischemia induction and during peak neovascularization (24), respectively ( Figure 2, A and B).…”

Section: Resultsmentioning

confidence: 99%

“…To induce OIR, we exposed wild-type pups to either 75% oxygen for 5 days (21) or 85% oxygen for 3 days (24). We analyzed Vegfa isoform expression in the retina on days 1 and 5 after return to normoxia, i.e., shortly after ischemia induction and during peak neovascularization (24), respectively ( Figure 2, A and B). As expected, both OIR protocols significantly increased Vegfa expression ( Figure 2C and Supplemental Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

VEGF188 promotes corneal reinnervation after injury

Brash¹,

Denti²,

Ruhrberg³

et al. 2019

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“…Mice were placed in hyperoxia at 85% O 2 from P8 to P11, as previously described [15]. Nursing mothers were rested at room air for 2-4 h daily.…”

Section: Oir Protocolmentioning

confidence: 99%

Stabilization of myeloid-derived HIFs promotes vascular regeneration in retinal ischemia

et al. 2019

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The retinal vasculature is tightly organized in a structure that provides for the high metabolic demand of neurons while minimizing interference with incident light. The adverse impact of retinal vascular insufficiency is mitigated by adaptive vascular regeneration but exacerbated by pathological neovascularization. Aberrant growth of neovessels in the retina is responsible for impairment of sight in common blinding disorders including retinopathy of prematurity, proliferative diabetic retinopathy, and age-related macular degeneration. Myeloid cells are key players in this process, with diverse roles that can either promote or protect against ocular neovascularization. We have previously demonstrated that myeloid-derived VEGF, HIF1, and HIF2 are not essential for pathological retinal neovascularization. Here, however, we show by cell-specific depletion of Vhl in a mouse model of retinal ischemia (oxygen-induced retinopathy, OIR) that myeloid-derived HIFs promote VEGF and bFGF expression and enhance vascular regeneration in association with improved density and organization of the astrocytic network.

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Accelerated oxygen-induced retinopathy is a reliable model of ischemia-induced retinal neovascularization

Cited by 14 publications

References 12 publications

The Pericytic Phenotype of Adipose Tissue-Derived Stromal Cells Is Promoted by NOTCH2

The Pericytic Phenotype of Adipose Tissue-Derived Stromal Cells Is Promoted by NOTCH2

VEGF188 promotes corneal reinnervation after injury

Stabilization of myeloid-derived HIFs promotes vascular regeneration in retinal ischemia

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