Purchase this article with an account.
Hua Liu, Yonju Ha, Shuang Zhu, Fan Xia, Wenbo Zhang; The dual roles of Epac1 in a mouse model of oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5473. doi: https://doi.org/.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP) is the leading cause of vision impair and blindness in childhood. A main clinic feature of ROP is the development of retinal avascularity followed by ischemia-driven retinal neovascularization (NV). Epac1, a novel mediator of cAMP, has been implicated in many pathological conditions. This study was to investigate the roles of Epac1 in ROP.
A mouse ROP model–oxygen-induced retinopathy (OIR) was induced. Epac1 expression and activity were examined by Western blot and immunostaining. NV and avascular area was analyzed with isolectin B4 staining in retinal flatmounts at P17. Retinal thickness and neuronal injury were assessed in retinal sections by H&E staining and TUNEL assay at P14. The mRNA levels of angiogenic factors were measured by real-time PCR. Epac inhibitor ESI-09 (i.p. 20 mg/kg/day) or vehicle was administrated to pups daily from P12 to P16. Integrin β1 (ITGB1) neutralizing antibody was injected intravitreally at P12. Retinal explant, primary mice retinal ganglion cells and human retinal microvascular endothelial cells (HRMECs) were used for in vitro studies.
Epac1 expression and its activity was increased in OIR retinas at various time points. Deleting Epac1 but not Epac2, or blocking Epac activation with inhibitor (ESI-09) significantly decreased retinal pathological NV while dramatically increasing physiological vascular repair at P17. Moreover, Epac1 deletion reduced neuronal cell death and preserved retina thickness, associated with decreases of OIR-induced angiogenic factors, including Angiopiontin2 and DII-4. In contrast, activating Epac by its agonist 007-AM induced retinal neuronal death in retinal explants or primary retinal ganglion cells. In addition, Epac1 expression was increased in neovascular tufts. Endothelial-specific deletion of Epac1 moderately decreased NV, but to a less extent than global deletion. Activating Epac in HRMECs enhanced their angiogenic ability (e.g. invasion, tube formation) in an ITGB1-dependent manner. Meanwhile, intravitreal blockade of ITGB1 attenuated retinal neovascularization.
Epac1 activation in retinal neurons and endothelial cells plays causal roles in inducing retinal neuronal injury, impairing vascular repair and promoting retinal pathological NV in OIR. Epac1 may be a potential target for the prevention and treatment of ROP.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
This PDF is available to Subscribers Only