Effect of vascular endothelial growth factor upregulation on retinal gene expression in the Kimba mouse

Binz, N.; Rahman, Ireni S. Ali; Chinnery, Holly R.; McKeone, Richard; Simpson, Ken M.; Speed, Terence P.; Lai, Chooi-May; Rakoczy, P. Elizabeth

doi:10.1111/j.1442-9071.2012.02845.x

Cited by 11 publications

(13 citation statements)

References 40 publications

(65 reference statements)

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“…Lack of Edn2 upregulation thus accounts for the difference in endothelin protein content between WT and Esr2-Edn2KO mice at hCG12 hours. Multiple attempts at immunohistochemical localization of EDN2 using anti-EDN2 antibody (Abcam 197763) 55 did not produce specific staining results (Figure S2). IHC staining was similar between WT, global Edn2KO, and granulosa cell-specific Edn2KO tissues and did not match phenotypic defects observed in global Edn2KO mice (expiration at eight days of age).…”

Section: Resultsmentioning

confidence: 99%

Granulosa cell endothelin-2 expression is fundamental for ovulatory follicle rupture

Cacioppo

Lin

Hannon

et al. 2017

Sci Rep

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Ovulation is dependent upon numerous factors mediating follicular growth, vascularization, and ultimately oocyte release via follicle rupture. Endothelin-2 (EDN2) is a potent vasoconstrictor that is transiently produced prior to follicle rupture by granulosa cells of periovulatory follicles and induces ovarian contraction. To determine the role of Edn2 expression, surgical transplant and novel conditional knockout mice were super-ovulated and analyzed. Conditional knockout mice utilized a new iCre driven by the Esr2 promoter to selectively remove Edn2. Follicle rupture and fertility were significantly impaired in the absence of ovarian Edn2 expression. When ovaries of Edn2KO mice were transplanted in wild type recipients, significantly more corpora lutea containing un-ovulated oocytes were present after hormonal stimulation (1.0 vs. 5.4, p = 0.010). Following selective ablation of Edn2 in granulosa cells, Esr2-Edn2KO dams had reduced oocytes ovulated (3.8 vs. 16.4 oocytes/ovary) and smaller litters (4.29 ± l.02 vs. 8.50 pups/dam). However, the number of pregnancies per pairing was not different and the reproductive axis remained intact. Esr2-Edn2KO ovaries had a higher percentage of antral follicles and fewer corpora lutea; follicles progressed to the antral stage but many were unable to rupture. Conditional loss of endothelin receptor A in granulosa cells also decreased ovulation but did not affect fecundity. These data demonstrate that EDN2-induced intraovarian contraction is a critical trigger of normal ovulation and subsequent fecundity.

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Section: Resultsmentioning

confidence: 99%

Granulosa cell endothelin-2 expression is fundamental for ovulatory follicle rupture

Cacioppo

Lin

Hannon

et al. 2017

Sci Rep

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“…33,34 Recently, we reported a reduction of VEGF gene expression in the retina of OXYS rats compared to the parent Wistar strain (control) during retinopathy progression 12 ; this effect may be linked to the early alterations in RPE cells and choroid vessels in OXYS rats. We supposed that such changes are prerequisite to the development of retinopathy and that their reversal is necessary for the prevention of the disease.…”

Section: Discussionmentioning

confidence: 99%

The mitochondria-targeted antioxidant SkQ1 restoresαB-crystallin expression and protects against AMD-like retinopathy in OXYS rats

et al. 2014

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Abbreviations: AMD, age-related macular degeneration; RPE, retinal pigment epithelium; SkQ1, 10-(6 0 plastoquinonyl)decyltriphenylphosphonium.Age-related macular degeneration (AMD), a neurodegenerative and vascular retinal disease, is the leading cause of blindness in the developed world. Accumulating evidence suggests that alterations in the expression of a small heat shock protein (aB-crystallin) are involved in the pathogeneses of AMD. Here we demonstrate that senescenceaccelerated OXYS rats-an animal model of the dry form of AMD-develop spontaneous retinopathy against the background of reduced expression of aB-crystallin in the retina at the early preclinical stages of retinopathy (age 20 days) as well as at 4 and 24 months of age, during the progressive stage of the disease. The level of aA-crystallin expression in the retina of OXYS rats at all the ages examined was no different from that in disease-free Wistar rats. Treatment with the mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from 1.5 to 4 months of age, 250 nmol/kg, increased the level of aB-crystallin expression in the retina of OXYS rats. SkQ1 slowed the development of retinopathy and reduced histological aberrations in retinal pigment epithelium cells. SkQ1 also attenuated neurodegenerative changes in the photoreceptors and facilitated circulation in choroid blood vessels in the retina of OXYS rats; this improvement was probably linked with the restoration of aB-crystallin expression.

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“…The heterozygous Akita male mice develop features similar to early pathophysiological changes of diabetic complications, but fail to exhibit the advanced stage vascular dysfunctions. The non-diabetic Kimba (trVEGF029) mouse model, in which photoreceptors transiently overexpress hVEGF, is characterized by several early and advanced DR-associated vascular changes such as vascular permeability, capillary non-perfusion, microaneurysms and retinal neovascularization [119,[122][123][124][125][126][127]. It has been reported that the combination of high blood glucose levels and VEGF overexpression exacerbates the vascular complications in the Akimba mouse eye [119,127].…”

Section: Transgenic Akimba Mouse Modelmentioning

confidence: 99%

“…The aforementioned vascular and inflammatory pathogenic pathways appear to be interlinked with neurodegeneration processes. In the Akimba mouse retinal thinning was observed and this was mainly associated to extensive degeneration of the photoreceptor layer and loss of retinal ganglion cells [119,124,128]. Finally, fibrosis pathogenic pathways can also be studied in the Akimba mouse model given that a substantial amount of fibrotic tissue was observed in the retinas of the majority of the old Akimba mice [119].…”

Section: Transgenic Akimba Mouse Modelmentioning

confidence: 99%

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

Geert¹,

Tjing-Tjing²

2016

J Mol Genet Med

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Diabetic Retinopathy (DR) is the most common microvascular complication of diabetes and is one of the leading causes of visual impairment worldwide. DR is a chronic eye disease that eventually can result in legal blindness due to the evolution towards the major vision-threatening disorders diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR). Current treatments with steroids, anti-VEGF compounds or retinal laser photocoagulation have shown a significant improvement in visual acuity in the advanced stage of the disease. However, main concerns are possible side effects and/or the relatively large number of clinical non-responders. A better understanding of the biological and molecular pathways not only in DR patients but also in the preclinical in vivo models would aid the development of novel and more efficient (personalized) therapeutic approaches for DR. This review aims to describe the pathways in a selection of diabetic, non-diabetic and surrogate rodent models of pathogenic neovascularization, vascular permeability, inflammation and neurodegeneration. None of these models can mimic the entire human pathophysiological progression but they all exhibit joint pathophysiological features with human DR pathogenesis. These combined features make these models very relevant in gaining a better understanding of the disease etiology and eventually improved strategies for drug screening. Through highlighting the most important biochemical and molecular pathways that these animal models have in common with DR patients, selection of the most suitable model for mechanistic studies and drug screening can be facilitated.

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Effect of vascular endothelial growth factor upregulation on retinal gene expression in the Kimba mouse

Cited by 11 publications

References 40 publications

Granulosa cell endothelin-2 expression is fundamental for ovulatory follicle rupture

Granulosa cell endothelin-2 expression is fundamental for ovulatory follicle rupture

The mitochondria-targeted antioxidant SkQ1 restoresαB-crystallin expression and protects against AMD-like retinopathy in OXYS rats

Selection Strategy of In Vivo Models for Ophthalmic Drug Development in Diabetic Retinopathy

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