Retinal Vascular Rescue of Oxygen-Induced Retinopathy in Mice by Norrin

Tokunaga, Clayton; Chen, Yi-Hao; Dailey, Wendy; Cheng, Mei; Drenser, Kimberly A.

doi:10.1167/iovs.12-10127

Cited by 26 publications

(24 citation statements)

References 30 publications

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“…DKK1 treatment is known to decrease retinal tuft formation in a rat OIR model by inhibiting Wnt canonical signaling [30]. In our OIR model, DKK1 Tg mice displayed decreased retinal vessel density (84 % of wild-type levels) and increased avascular area (187 % of wild-type), in agreement with earlier observations in rats (Fig.…”

Section: Resultssupporting

confidence: 92%

Distinct roles of DKK1 and DKK2 in tumor angiogenesis

et al. 2013

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Tumor angiogenesis is essential for tumor invasive growth and metastasis, and generates abnormal vascular structures unlike developmental neovessel formation. To reduce tumor vascular abnormalities such as leakage and perivascular cell coverage deficiency that limit cancer therapy effectiveness, novel therapeutic approaches focus on vessel normalization. We have previously shown that Dickkopf-1 (DKK1), a Wnt antagonist, inhibits and its homolog DKK2 enhances, angiogenesis in normal tissues. In the present study, we investigated the effects of DKK1 and DKK2 on tumor growth and angiogenesis. Treatment of B16F10 melanoma-bearing mice with adenovirus expressing DKK1 significantly reduced tumor growth but DKK2 increased growth compared with controls. Similar pattern of tumor growth was observed in endothelial-specific DKK1 and DKK2 transgenic mice. Interestingly, tumor vascular density and perfusion were significantly decreased by DKK1 but increased by DKK2. Moreover, coverage of blood vessels by pericytes was reduced by DKK1, while DKK2 increased it. We further observed that DKK1 diminished retinal vessel density and increased avascular area in an in vivo murine model of oxygen-induced retinopathy, whereas DKK2 showed opposite results. These findings demonstrate that DKK1 and DKK2 have differential roles in normalization and functionality of tumor blood vessels, in addition to angiogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-013-9390-5) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 92%

Distinct roles of DKK1 and DKK2 in tumor angiogenesis

et al. 2013

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“…This disorganization is likely the result of a substantial percentage of retinal astrocytes and the fact that surviving astrocytes are impaired in their capacity to guide capillary growth (Bucher et al, 2013). In this environment, treatment with Norrin somewhat tames neovascular response and ultimately accelerates the revascularization of the central retina (Tokunaga et al, 2013). Other treatments have been reported that reduce the severity of aggressive neovascular growth in this model and facilitate re-establishment of normal vascular beds in ablated zones (May, 2012)…”

Section: Discussionmentioning

confidence: 99%

“…The oxygen-induced retinopathy (OIR) model using C57BL/6J or Thy1 -YFP transgenic mice neonates was used as previously described (Smith et al, 1994; Tokunaga et al, 2014, 2013). This model is well characterized and widely used for experimental studies of retinal ischemia (Smith et al, 1994).…”

Section: Methodsmentioning

confidence: 99%

“…This causes ablation of vascular beds in the central retina that leads to a state of ischemia when the mice are returned to normal room air, which is 21% oxygen (Lange et al, 2009; Scott et al, 2014; Smith et al, 1994). We and others have shown that intravitreal injection of Norrin, a Wnt-signaling ligand, promotes earlier re-vascularization of the OIR retina as well as reduced neovascularization (Ohlmann et al, 2010; Tokunaga et al, 2013). We know that ischemia has a destructive effect upon ganglion cells (Kaur et al, 2008) and Norrin has been shown to be neuroprotective to RGCs in a mouse model of excitotoxic RGC damage (Seitz et al, 2010).…”

Section: Introductionmentioning

confidence: 95%

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Norrin treatment improves ganglion cell survival in an oxygen-induced retinopathy model of retinal ischemia

Dailey

Drenser

Wong

et al. 2017

Experimental Eye Research

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Treatment of a mouse model of oxygen-induced retinopathy (OIR) with recombinant human Norrin (Norrie Disease Protein, gene: NDP) accelerates regrowth of the microvasculature into central ischemic regions of the neural retina, which are generated after treatment with 75% oxygen. While this reduces the average duration and severity of ischemia overall, we do not know if this accelerated recovery of the microvasculature results in any significant survival of retinal ganglion cells (RGCs). The purpose of this study was to investigate ganglion cell survival with and without the intravitreal injection of Norrin in the murine model of oxygen induced retinopathy (OIR), using two strains of mice: C57BL/6J and Thy1-YFP mice. Intravitreal injections of Norrin or vehicle were done after five days of exposure to 75% oxygen from ages P7 to P12. The C57BL/J mice were followed by Spectral-Domain Optical Coherence Tomography (SD-OCT), and the average nerve fiber layer (NFL) and inner-plexiform layer (IPL) thicknesses were measured at twenty-four locations per retina at P42. Additionally, some C57BL/J retinas were flat mounted and immunostained for the RGC marker, Brn3a, to compare the population density of surviving retinal ganglion cells. Using homozygous Thy1-YFP mice, single intrinsically fluorescent RGCs were imaged in live animals with a Micron-III imaging system at ages P21, 28 and P42. The relative percentage of YFP-fluorescent RGCs with dendritic arbors were compared. At age P42, the NFL was thicker in Norrin-injected OIR eyes, 14.4 μm, compared to Vehicle-injected OIR eyes, 13.3 μm (p=0.01). In the superior retina, the average thickness of the IPL was greater in Norrin-injected OIR eyes, 37.7 μm, compared to Vehicle-injected OIR eyes, 34.6 μm (p = 0.04). Retinas from Norrin injected OIR mice had significantly more surviving RGCs (p = 0.03) than vehicle-injected mice. Based upon NFL thickness and counts of RGCs, we conclude that Norrin treatment, early in the ischemic phase, increased the relative population density of surviving RGCs in the central retinas of OIR mice.

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“…Comparatively, the PBS-treated eyes had a significant decrease (20%) in the avascular area compared with the noninjected fellow eyes (P ¼ 0.016), an effect seen previously as well. 18,19 Retinal recovery can occur in response to injury such as that caused by an intravitreal injection. It is feasible that low-grade inflammation following ocular penetration may have a role in retinal recovery.…”

Section: Avascular Areamentioning

confidence: 99%