Temporal requirement of RPE‐derived VEGF in the development of choroidal vasculature

Le, Yun-Zheng; Bai, Yanyan; Zhu, Meili; Zheng, Lixin

doi:10.1111/j.1471-4159.2010.06573.x

Cited by 46 publications

(39 citation statements)

References 40 publications

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“…RPE cells express high amounts of VEGF during embryonic development and in adult life (Ford et al 2011), which are essential for both the formation and the maintenance of the choriocapillaris. Conditional VEGF deficiency in the developing RPE results in the absence of the choriocapillaris in mutant mice (Marneros et al 2005;Le et al 2010), and conditional deletion of VEGF in the adult mouse RPE rapidly leads to ablation of the choriocapillaris . In addition, mutant mice that only express the VEGF188 isoform of VEGF, which does not readily diffuse from the RPE across Bruch's membrane to reach the choroidal vessels, similarly suffer from atrophy of the choriocapillaris (SaintGeniez et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Ohlmann

Scholz

Koch

et al. 2016

Histochem Cell Biol

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Epithelial-to-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is commonly observed at sites of choroidal neovascularization in patients suffering from age-related macular degeneration. To learn in an experimental model how RPE EMT affects the biology of the choroidal vasculature, we studied transgenic mice (βB1-TGF-β1) with ocular overexpression of transforming growth factor-β1 (TGF-β1). RPE EMT was detectable at postnatal day (P)1 and included marked structural and functional alterations such as loss of the outer blood-retina barrier and reduced mRNA expression of the RPE-characteristic molecules Rlbp1, Rpe65, Rbp1 and Vegfa. Moreover, vascular endothelial growth factor (VEGF) was not detectable by immunohistochemistry at the RPE/choroid interface, while RPE cells stained intensely for α-smooth muscle actin. The choriocapillaris, the characteristic choroidal capillary network adjacent to the RPE, developed normally and was not obviously changed in embryonic transgenic eyes but was absent at P1 indicating its atrophy. At around the same time, photoreceptors stopped to differentiate and photoreceptor apoptosis was abundant in the second week of life. Structural changes were also seen in the retinal vasculature of transgenic animals, which did not form intraretinal vessels, and the hyaloid vasculature, which did not regress. In addition, the amounts of retinal HIF-1α and its mRNA were markedly reduced. We conclude that high amounts of active TGF-β1 in the mouse eye cause transdifferentiation of the RPE to a mesenchymal phenotype. The loss of epithelial differentiation leads to the diminished synthesis of RPE-characteristic molecules including that of VEGF. Lack of RPE-derived VEGF causes atrophy of the choriocapillaris, a scenario that disrupts photoreceptor differentiation and finally results in photoreceptor apoptosis. Lack of retinal vessel formation and of hyaloid vessel regression might be caused by the decrease in the metabolic requirements of the neuroretina leading to low amounts of retinal HIF-1α. In summary, our data indicate that failure of RPE differentiation may well precede and cause atrophy of the choriocapillaris. In contrast, RPE EMT is not sufficient to cause choroidal neovascularization.

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Section: Discussionmentioning

confidence: 99%

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Ohlmann

Scholz

Koch

et al. 2016

Histochem Cell Biol

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“…21 The disruption of RPEderived VEGF after E15 using conditional VEGF knockout (KO) mice with an inducible Cre/lox system did not cause detectable developmental defects. 22 VEGF is known to be regulated by multiple transcription factors and pathways. 23 To determine the role of RPE-derived HIF-1 in ischemia-induced VEGF over production and ocular NV, we knocked out HIF-1a in the RPE using the Cre/lox system.…”

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confidence: 99%

Impacts of Hypoxia-Inducible Factor-1 Knockout in the Retinal Pigment Epithelium on Choroidal Neovascularization

Lin¹,

Hu²,

Chen³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Hypoxia-inducible factor (HIF)-1 is a key oxygen sensor and is believed to play an important role in neovascularization (NV). The purpose of this study is to determine the role of retinal pigment epithelium (RPE)-derived HIF-1a on ocular NV. METHODS.Conditional HIF-1a knockout (KO) mice were generated by crossing transgenic mice expressing Cre in the RPE with HIF-1a floxed mice, confirmed by immunohistochemistry, Western blot analysis, and fundus fluorescein angiography. The mice were used for the oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models.RESULTS. HIF-1a levels were significantly decreased in the RPE layer of ocular sections and in primary RPE cells from the HIF1a KO mice. Under normal conditions, the HIF-1a KO mice exhibited no apparent abnormalities in retinal histology or visual function as shown by light microscopy and electroretinogram recording, respectively. The HIF-1a KO mice with OIR showed no significant difference from the wild-type (WT) mice in retinal levels of HIF-1a and VEGF as well as in the number of preretinal neovascular cells. In the laser-induced CNV model, however, the disruption of HIF-1a in the RPE attenuated the over expression of VEGF and the intercellular adhesion molecule 1 (ICAM-1), and reduced vascular leakage and CNV area.CONCLUSIONS. RPE-derived HIF-1a plays a key role in CNV, but not in ischemia-induced retinal NV. (Invest Ophthalmol Vis Sci.

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“…However, the advent of tissue-specific gene manipulation in mouse models has enabled better understanding of VEGF and receptor function. Depletion of VEGF in skeletal muscle [34], lung [35], and retina [36] can produce a variety of pathological phenotypes associated with perturbation of vascular function in these tissues. A mechanistic framework towards understanding VEGF function is that high affinity homo-and heteromeric receptor complexes bind different VEGFs and transduce signals that regulate cellular physiology including cell survival, migration, proliferation, angiogenesis, and vasculogenesis.…”

Section: Vegf Function In Higher Eukaryotesmentioning

confidence: 99%

Evolution of the VEGF-Regulated Vascular Network from a Neural Guidance System

Ponnambalam

Alberghina

2011

Mol Neurobiol

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The vascular network is closely linked to the neural system, and an interdependence is displayed in healthy and in pathophysiological responses. How has close apposition of two such functionally different systems occurred? Here, we present a hypothesis for the evolution of the vascular network from an ancestral neural guidance system. Biological cornerstones of this hypothesis are the vascular endothelial growth factor (VEGF) protein family and cognate receptors. The primary sequences of such proteins are conserved from invertebrates, such as worms and flies that lack discernible vascular systems compared to mammals, but all these systems have sophisticated neuronal wiring involving such molecules. Ancestral VEGFs and receptors (VEGFRs) could have been used to develop and maintain the nervous system in primitive eukaryotes. During evolution, the demands of increased morphological complexity required systems for transporting molecules and cells, i.e., biological conductive tubes. We propose that the VEGF-VEGFR axis was subverted by evolution to mediate the formation of biological tubes necessary for transport of fluids, e.g., blood. Increasingly, there is evidence that aberrant VEGF-mediated responses are also linked to neuronal dysfunctions ranging from motor neuron disease, stroke, Parkinson's disease, Alzheimer's disease, ischemic brain disease, epilepsy, multiple sclerosis, and neuronal repair after injury, as well as common vascular diseases (e.g., retinal disease). Manipulation and correction of the VEGF response in different neural tissues could be an effective strategy to treat different neurological diseases.

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Temporal requirement of RPE‐derived VEGF in the development of choroidal vasculature

Cited by 46 publications

References 40 publications

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Impacts of Hypoxia-Inducible Factor-1 Knockout in the Retinal Pigment Epithelium on Choroidal Neovascularization

Evolution of the VEGF-Regulated Vascular Network from a Neural Guidance System

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