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Chintan Patel, Wenbo Zhang, S. Priya Narayanan, Zhimin Xu, Robert William Caldwell, Ruth B Caldwell; Endothelin, a novel angiogenic factor in ischemic retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5392.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) adversely affects premature infants due to oxygen-induced damage of the immature retinal vasculature resulting in pathological neovascularization (NV). Studies using the mouse model of oxygen-induced retinopathy (OIR) indicate that interplay of factors such as VEGF, EPO, angiopoietins, MCP-1 and others is critically involved in the pathogenesis of the ROP. We previously showed that endothelins, known as potent vasoconstrictors, are highly involved in OIR and are largely responsible for pathological angiogenesis. Here we show that activation of the endothelin system via the ETA receptor induces pathological NV by a mechanism involving increased STAT3 activation, VEGF expression and production of angiogenic factors.
Mice were exposed to 75% oxygen from postnatal day P7 to P12, treated with either vehicle or ETA receptor antagonist (BQ-123, 17 ug/uL, intravitreal injection) and returned to room air from P12 to P17. Retinas were processed to study angiogenesis and assess expression of endothelin system components and angiogenic factors.
RT-PCR analysis revealed significant increases in ET-1, ET-2 and ETA receptor mRNA expression during ischemia. Treatment of OIR mice with BQ-123 significantly increased numbers of tip cells resulting in enhancement of physiological angiogenesis, improved vascular repair and decreased pathological NV. OIR triggered a significant increase in phosphorylation of STAT3 and VEGF production compared to room-air control. Both effects were abrogated by BQ-123 treatment, suggesting that endothelin signaling via the ETA receptor mediates VEGF production, possibly through STAT3 activation. OIR also increased mRNA expression of Delta-like ligand (Dll) 4, apelin, angiopoietin-2, endothelial-specific molecule-1 or endocan and MCP-1, which were all reduced by blockade of the ETA receptor.
Inhibition of the ETA receptor during OIR promoted physiological angiogenesis and suppressed pathological NV. In addition, blockade of ETA receptor reversed misdirected vessel growth by enhancing tip cell formation at the leading edges of neovessel formation and reducing ischemia-induced angiogenic modulators. Neutralizing the actions of endothelins may provide an effective approach to resolving pathological NV and enhancing vision of patients with retinopathy of prematurity.
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