Abstract
Purpose: :
Abnormal and disproportionate vascular proliferation is central to of prematurity (ROP), an important cause of visual impairment in children. Insulin-like growth factor (IGF-1) is a significant permissive factor in retinal angiogenesis. IGF-1 is regulated to a significant extent by ghrelin via the growth hormone secretagogue receptor 1a (GHSR-1a). We explored vasoproliferative properties of ghrelin acting via GHSR-1a, in particular those related to retinal neovascularization.
Methods: :
The expression and localization of GHSR-1a was examined in the rat retina and in various isolated retinal cell cultures (WB and IHC). The effects on retinal vascular preservation of the stable ghrelin anlogue Dap-ghrelin and the GSHR-1a antagonist JMV-2959, were determined in vivo in lectin stained, flat-mounted retinas of rats subjected to a model of oxygen-induced retinopathy (OIR) (P5-P10 in 80% oxygen). Retinal vessel growth rates were assayed in pups injected intravitreally at P1 and assayed at P6. The angiogenic properties of ghrelin and its receptor were confirmed in aortic ring sprouting assays and by thymidine incorporation in endotheial cells.
Results: :
GHSR-1a was found to be abundantly expressed in microvascular endothelial cells throughout the retina. In OIR (intravitreal) Dap-ghrelin significantly reduced areas of vessel loss and preserved vascular density, otherwise depleted in this model. Dap-ghrelin also enhanced developmental retinal vessel density. Conversely, treatment with the GHSR-1a antagonist, JMV-2959, almost completely reverted the pro-angiogenic effects of Dap-ghrelin. Angiogenic effects of Dap-ghrelin and conversely of its antagonist JMV-2959 were reproduced ex vivo on vascular sprouting of aortic explants and in vitro on endothelial cell proliferation.
Conclusions: :
We hereby disclose a new role for the ghrelin-GHSR-1a pathway in preservation of retinal vasculature in ROP/OIR through a growth hormone-independent process. Observations are likely to apply to various ischemic retinopathies, including that of diabetes.
Keywords: retinopathy of prematurity • receptors: pharmacology/physiology • ischemia