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Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor.

ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor, initially discovered for its role in regulating xenobiotic metabolism. There is extensive evidence supporting a multi-faceted role for AhR, modulating physiological pathways important in cell health and disease. Recently we demonstrated that the AhR plays a role in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that loss of AhR exacerbates choroidal neovascular (CNV) lesion formation in a murine model. Herein we tested the therapeutic impact of AhR activation on CNV lesion formation and factors associated with aberrant neovascularization. We screened a panel of synthetic drugs and endogenous AhR ligands, assessed their ability to activate AhR in choroidal endothelial cells, and inhibit angiogenesis in vitro. Drugs with an anti-angiogenic profile were then administered to a murine model of CNV. Two compounds, leflunomide and flutamide, significantly inhibited CNV formation concurrent with positive modifying effects on angiogenesis, inflammation, extracellular matrix remodeling, and fibrosis. These results validate the role of the AhR pathway in regulating CNV pathogenesis, identify mechanisms of AhR-based therapies in the eye, and argue in favor of developing AhR as a drug target for the treatment of neovascular AMD.

SUBMITTER: Choudhary M

PROVIDER: S-EPMC5880720 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor.

Choudhary Mayur M Safe Stephen S Malek Goldis G

Biochimica et biophysica acta. Molecular basis of disease 20180223 5 Pt A

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor, initially discovered for its role in regulating xenobiotic metabolism. There is extensive evidence supporting a multi-faceted role for AhR, modulating physiological pathways important in cell health and disease. Recently we demonstrated that the AhR plays a role in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that loss of AhR exacerbates choroid ...[more]

PMID: 29481912

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Project description:The aryl hydrocarbon receptor (AhR) is a heterodimeric transcriptional regulator with pleiotropic functions in xenobiotic metabolism and detoxification, vascular development and cancer. Herein, we report a previously undescribed role for the AhR signalling pathway in the pathogenesis of the wet, neovascular subtype of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly in the Western world. Comparative analysis of gene expression profiles of aged AhR(-/-) and wild-type (wt) mice, using high-throughput RNA sequencing, revealed differential modulation of genes belonging to several AMD-related pathogenic pathways, including inflammation, angiogenesis and extracellular matrix regulation. To investigate AhR regulation of these pathways in wet AMD, we experimentally induced choroidal neovascular lesions in AhR(-/-) mice and found that they measured significantly larger in area and volume compared to age-matched wt mice. Furthermore, these lesions displayed a higher number of ionized calcium-binding adaptor molecule 1-positive (Iba1(+) ) microglial cells and a greater amount of collagen type IV deposition, events also seen in human wet AMD pathology specimens. Consistent with our in vivo observations, AhR knock-down was sufficient to increase choroidal endothelial cell migration and tube formation in vitro. Moreover, AhR knock-down caused an increase in collagen type IV production and secretion in both retinal pigment epithelial (RPE) and choroidal endothelial cell cultures, increased expression of angiogenic and inflammatory molecules, including vascular endothelial growth factor A (VEGFA) and chemokine (C-C motif) ligand 2 (CCL2) in RPE cells, and increased expression of secreted phosphoprotein 1 (SPP1) and transforming growth factor-?1 (TGF?1) in choroidal endothelial cells. Collectively, our findings identify AhR as a regulator of multiple pathogenic pathways in experimentally induced choroidal neovascularization, findings that are consistent with a possible role of AhR in wet AMD. The data discussed in this paper have been deposited in NCBI's Gene Expression Omnibus; GEO Submission No. GSE56983, NCBI Tracking System No. 17021116.

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Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor.

Publications

Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor.

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