Progressive retinal degeneration in transgenic mice with overexpression of endothelin-1 in vascular endothelial cells.

PURPOSE Endothelin-1 (ET-1), synthesized in vascular endothelial cells, is a potent vasoconstrictor. ET-1-related vascular abnormality has been known to be important in the pathogenesis of glaucoma, especially in normal tension glaucoma. However, the long-term effect of increased vascular ET-1 on the retinal tissue is still unclear. METHODS The mice with overexpression of ET-1 in vascular endothelial cells (TET-1 mice) were examined with the profile of intraocular pressure (IOP), retinal layer thickness, numbers of retinal ganglion cells (RGCs), and axonal changes associated with blood vessel changes. RESULTS The TET-1 mice exhibited a significant progressive loss of RGCs and decrease of retinal thickness in the inner nuclear layer (INL) and outer nuclear layer (ONL) as early as around 10-12 months. At 24 months, the retinal degeneration became more severe, with around 30% RGC loss associated with thinning of the retinal nerve fiber layer and there was an increase in neuronal loss and thinning of the INL and ONL. In the 24-month-old TET-1 mice, IgG leakage in the blood vessels and decrease in the occludin protein were observed. There was increased glial fibrillary acidic protein expression in the Müller cells. In addition, the astrocytic end-feet on blood vessels were enlarged. The IOP level was normal in all ages (1-24 months) of TET-1 mice. CONCLUSIONS These data suggested that TET-1 mice may be a useful model to address endothelial ET-1-related mechanisms in vascular-associated retinal degenerative diseases.