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Nagaraj Kerur, Jayakrishna Ambati, Shaobin Wang, DAIPAYAN BANERJEE, Shuichiro Hirahara, Eric Odermatt; TELOMERASE IN CHOROIDAL NEOVASCULARIZATION. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4319. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Aberrant ocular angiogenesis underlies catastrophic loss vision due to multiple conditions including neovascular age-related macular degeneration (nvAMD), proliferative diabetic retinopathy (DR), retinopathy of prematurity (ROP), and ischemic retinal vein occlusion. Although anti-VEGF therapy has revolutionized the management of such disorders, the drugs suffer from several roadblocks. Prolonged anti-VEGF therapies are accompanied by serious risks and significant number of patients still experience vision loss despite treatment. Therefore, new insights into molecular mechanisms that promote angiogenesis in the retina are needed for the development of more effective therapies. Telomerase activity is reported to confer replicative potential to tumor and endothelial cells. Elevated levels of telomerase are observed in 90% of the human cancers. Telomerase is also reported to modulate several important proangiogenic cellular processes including Wnt signaling, PolI transcription, and induction of proangiogenic inflammatory cytokines. Despite extensive evidence supporting the role of telomerase in angiogenesis in cancer, its involvement in ocular pathological angiogenesis remains unexplored. We sought to define the proangiogenic potential of telomerase employing mouse model of laser-induced choroidal neovascularization (CNV) and cell culture.
Choroidal neovascularization (CNV) was induced by laser injury in 10-week old C57BL/6J wild-type, Terc+/– and Terc−/− mice, and CNV volume was measured after 7 days by confocal microscopy. Bone marrow derived macrophages (BMDM) from wild-type, Terc+/– and Terc−/− mice were exposed to hypoxia (1%). RNA isolated from control and hypoxia treated BMDMs were analyzed to examine the abundance of gene transcripts by RT-qPCR.
We observed significantly reduced angiogenic responses in the Terc–/–mice compared to WT and Terc+/– mice. Induction of angiogenesis-related gene transcripts (Vegf, Ang, and Mmp1) in response to hypoxia was dramatically reduced in Terc–/– BMDM compared to Terc+/–. Similarly, transcriptional induction of hypoxia-response genes (Pgk1, Ndrg1, P4ha, and Car9) was impaired in Terc–/– BMDM compared to Terc+/–.
Telomerase activity promotes ocular angiogenesis in mouse model of laser induced choroidal neovascularization.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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