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Helder Andre, Parviz Mammadzada, Anna Takei, Malena Ekstöm, Ma Yu, Monica Aronsson, Anders P Kvanta; Gene Transfer of Prolyl Hydroxylase Domain 2 Inhibits Hypoxia-inducible Angiogenesis in a Model of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2298.
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Cellular responses to hypoxia are mediated by the hypoxia-inducible factors (HIF). In normoxia, HIF-α proteins are tightly regulated by a family of dioxygenases, both by proteasomal-mediated degradation and transcriptional inactivation. In hypoxic conditions, the dioxygenases become inactive and allow formation of HIF transcription factor, responsible for the upregulation of a myriad of target genes. In ocular neoangiogenic diseases, such as neovascular age-related macular degeneration (nAMD), the role of ischemia and hypoxia is associated with progression of choroidal neovascularization. Here, we investigate the effects of HIF-regulating proteins on the hypoxia pathway in retinal pigment epithelium (RPE) cells, critically involved in nAMD pathogenesis.
ARPE-19 cells were transfected with HIF-regulating proteins. In vitro angiogenesis was assayed in human retinal and choroidal endothelial cells. In vivo analysis of the effects of HIF-regulating proteins was determined in mouse models of iris and choroidal induced angiogenesis.
Our previous results have associated HIF expression in RPE cells to CNV progression. Our data indicates that, in ARPE-19 cells, prolyl hydroxylase domain (PHD)2 is the most potent negative-regulator of the HIF pathway. Furthermore, the negative effects of PHD2 on the hypoxia pathway were associated with decreased HIF-1α protein levels, and concomitant decrease in secreted VEGF by these cells. Consequently, ARPE-19 cells stably expressing PHD2 impaired angiogenesis in endothelial cells, both in vitro and in vivo. Gene transfer of PHD2 in vivo resulted in mitigation of HIF-mediated angiogenesis in a mouse model of nAMD.
These results may have implications for the clinical treatment, particularly regarding the use of gene therapy to negatively regulate neoangiogenesis present in nAMD patients.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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