Modulation of VEGF-Induced Retinal Vascular Permeability by Peroxisome Proliferator-Activated Receptor- /

Suárez, Sandra; McCollum, Gary W.; Bretz, Colin A.; Yang, Rong; Capozzi, Megan E.; Penn, John S.

doi:10.1167/iovs.14-14217

Cited by 37 publications

(37 citation statements)

References 57 publications

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“…Claudin-1 is present in the tight junctions between endothelial cells of retinal vessels [26,27]. In addition, Claudin-1 gene expression is suppressed following VEGF treatment [28]. Our findings showed that hVEGF treatment decreased Claudin-1 levels while FGF21 co-treatment preserved Claudin-1 levels.…”

Section: Discussionmentioning

confidence: 51%

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

Tomita

Wang

et al. 2020

IJMS

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The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice were pre-treated with long-acting FGF21 analog or vehicle (Phosphate Buffered Saline; PBS) intraperitoneally (i.p.) before induction of retinal vascular leakage with intravitreal injection of mouse (m) vascular endothelial growth factor 164 (VEGF164) or PBS control. Five hours after mVEGF164 injection, we retro-orbitally injected Fluorescein isothiocyanate (FITC) -dextran and quantified fluorescence intensity as a readout of vascular leakage, using the Image Analysis Module with a machine learning algorithm. In FGF21-or vehicle-treated primary human retinal microvascular endothelial cells (HRMECs), cell permeability was induced with human (h) VEGF165 and evaluated using FITC-dextran and trans-endothelial electrical resistance (TEER). Western blots for tight junction markers were performed. Retinal vascular leakage in vivo was reduced in the FGF21 versus vehicletreated mice. In HRMECs in vitro, FGF21 versus vehicle prevented hVEGF-induced increase in cell permeability, identified with FITC-dextran. FGF21 significantly preserved TEER compared to hVEGF. Taken together, FGF21 regulates permeability through tight junctions; in particular, FGF21 increases Claudin-1 protein levels in hVEGF-induced HRMECs. Long-acting FGF21 may help reduce retinal vascular leakage in retinal disorders and machine learning assessment can help to standardize vascular leakage quantification.

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Section: Discussionmentioning

confidence: 51%

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

Tomita

Wang

et al. 2020

IJMS

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“…Modeling retinal neovascularization, it was shown that pharmacological antagonism of PPARβ/δ significantly decreased serum-induced retinal endothelial cell proliferation and tube formation in a dose-dependent manner, and in vivo decreased retinal neovascularization in young rats. Another study from the same group showed that pharmacological antagonism of PPARβ/δ stabilized tight junctions in retinal microvascular endothelial cells treated with VEGF, and reduced VEGFR1/2 expression, suggesting a role in retinal vascular permeability [ 52 ]. The present study examined the effect of ligand activation and pharmacological antagonism of PPARβ/δ on choroidal neovascularization, in which the highly fenestrated choriocapillaris; vasculature supporting the outer retina; grow through Bruch's membrane under the RPE, in vivo , using a laser-induced CNV model.…”

Section: Discussionmentioning

confidence: 99%

PPARβ/δ selectively regulates phenotypic features of age-related macular degeneration

Choudhary

Ding

et al. 2016

Aging

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Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a nuclear receptor that regulates differentiation, inflammation, lipid metabolism, extracellular matrix remodeling, and angiogenesis in multiple tissues. These pathways are also central to the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss globally. With the goal of identifying signaling pathways that may be important in the development of AMD, we investigated the impact of PPARβ/δ activation on ocular tissues affected in the disease. PPARβ/δ is expressed and can be activated in AMD vulnerable cells, including retinal pigment epithelial (RPE) and choroidal endothelial cells. Further, PPARβ/δ knockdown modulates AMD-related pathways selectively. Specifically, genetic ablation of Pparβ/δ in aged mice resulted in exacerbation of several phenotypic features of early dry AMD, but attenuation of experimentally induced choroidal neovascular (CNV) lesions. Antagonizing PPARβ/δ in both in vitro angiogenesis assays and in the in vivo experimentally induced CNV model, inhibited angiogenesis and angiogenic pathways, while ligand activation of PPARβ/δ, in vitro, decreased RPE lipid accumulation, characteristic of dry AMD. This study demonstrates for the first time, selective regulation of a nuclear receptor in the eye and establishes that selective targeting of PPARβ/δ may be a suitable strategy for treatment of different clinical sub-types of AMD.

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“…Each well was transfected, as previously described81, with 200 ng NFkB-responsive luciferase constructs from the Cignal NFkB Reporter Assay (Qiagen). Cells were treated with vehicle or TNFα (1 ng/ml) in the presence or absence of 11,12-EET (0.5 μM) or 19,20-EDP (0.5 μM) with AUDA (10 μ M) for 24 hours after initiating transfection.…”

Section: Methodsmentioning

confidence: 99%

Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation

Capozzi

Hammer

McCollum

et al. 2016

Sci Rep

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The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.

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Modulation of VEGF-Induced Retinal Vascular Permeability by Peroxisome Proliferator-Activated Receptor- /

Cited by 37 publications

References 57 publications

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

PPARβ/δ selectively regulates phenotypic features of age-related macular degeneration

Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation

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