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Chintan Patel, Wenbo Zhang, Zhimin Xu, S. P. Narayanan, Nai-tse Tsai, William Caldwell, Ruth B. Caldwell; Activation of the Endothelin System in Models of Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6296.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies in models of cardiovascular disease and cancer have shown that activation of the endothelin (ET) receptors ETA and ETB by ET-1 increases HIF-1α-mediated VEGF expression. ET is a potent vasoconstrictor that acts via ET receptors to induce Ca2+ signaling, PKC activation and expression of mitogenic factors. Activation of the ET system has been implicated in glaucoma. However, the role of ET system in retinal vascular injury and neovascularization is completely unknown.
For in vivo studies, mice were exposed to 75% oxygen from postnatal day P7 to P12, returned to room air from P12-P17 and retinas were collected on P17 for RT-PCR to study the expression of ET system components. Hyperoxia-treated mice were injected intravitreally with either vehicle or ETA receptor antagonist (BQ-123, 17 ug/uL) on P12 and retinas were processed to study angiogenesis and cytokine formation. ET-induced angiogenic response was studied in vitro in a matrigel tube-formation assay. To study ET-mediated changes in VEGF protein expression, primary cultures of bovine retinal endothelial cells (BRE) and rat Muller cells were treated with ET-1 and ET-2 (10nM).
RT-PCR analysis revealed significant increases in ET-1, ET-2 and ETA receptor mRNA expression and in ET protein levels during retinal ischemia. Treatment with BQ-123 significantly enhanced vascular repair (3 fold), inhibited pathological NV (10 fold) and reduced production of angiogenic and inflammatory factors such as angiopoietin-2, endothelial cell-specific molecule-1, iNOS, MCP-1, and ICAM-1. ET-1 or ET-2 treatment of cultured endothelial cells promoted tube formation in a matrigel assay (2 fold). Treatment of BRE and Muller cells with ET-1 or ET-2 induced time-dependent increases in STAT3 activation and VEGF expression as shown by Western blot analysis (2 and 2-fold, respectively).
Blockade of ETA may be effective in promoting vascular repair during ischemic retinopathy. ET’s can enhance production of VEGF via a mechanism involving STAT3 activation. Hence, blockade of the ETA receptor may prove to be an effective therapy for ischemic retinopathy.
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