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1 From the Department of Pharmacology and Neuroscience and the 3 Department of Anatomy & Pathology, Division of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas; and 2 Glaucoma Research, Alcon Laboratories Ltd., Fort Worth, Texas.
PURPOSE. To determine whether human optic nerve head astrocytes (hONAs) are target cells for the actions of endothelin (ET)-1, a potent vasoactive peptide, by causing astrocyte proliferation, as occurs in glaucomatous optic nerve heads. ET-1 levels are elevated in glaucomatous eyes, and administration of ET-1 to the retina causes glial activation and optic nerve damage in animal models in a manner similar to that observed in glaucoma.
METHODS. Well-characterized hONAs were used in this study. Cell proliferation of hONAs was assessed, after ET-1 treatment under serum-free culture conditions, with both a formazan assay and [3H]thymidine uptake. ET receptor involvement for cell proliferation was determined with BQ788 (an ETB antagonist), BQ610 (an ETA antagonist), PD142893 (an ETA/B mixed antagonist), and sarafotoxin 6C (S6C; an ETB agonist). ET-1–induced intracellular calcium ([Ca2+]i) in hONAs was measured by fura-2 imaging. RT-PCR was used to determine whether hONAs express mRNA for preproET-1, ETA, and ETB receptors.
RESULTS. ET-1 (10 and 100 nM) caused a time-dependent proliferation of hONAs, which was completely blocked by PD142893, as detected by two different cell proliferation assays. The effects of ET-1 were blocked by BQ788 and were also mimicked by S6C, indicative of the involvement of ETB receptor activation. ET-1–induced elevation in [Ca2+]i, and cell proliferation were both blocked completely by the ETA antagonist BQ610, suggesting ETA receptor involvement. The hONAs expressed mRNA for ETA and ETB receptors as well as preproET-1, suggesting that these cells may also be a source for ET-1 in the optic nerve head.
CONCLUSIONS. ET-1 induces astroglial proliferation in cultured human optic nerve head astrocytes through ETA/B receptor activation. This is similar to the proliferation of ET-1 in brain astrocytes. These findings suggest that ET-1, which is elevated in glaucoma, could cause proliferation of ONAs in the optic nerve head.
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