Purchase this article with an account.
S. Tremblay, P. Sapieha, K. Zaniolo, H. Fernandez, D. Hamel, S. Chemtob; A New Role for a Krebs Cycle Intermediate : -Ketoglutarate Promotes Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2949.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of prematurity (ROP), a major cause of blindness in developed countries, occurs in two phases : the cessation of normal eye development after birth and a subsequent abnormal and exagerated vessel growth. Recently, we presented a previously undisclosed role for the krebs cycle intermediate succinate and its cognate receptor GPR91 in the modulation of retinal vessel. Here we investigated the role of -ketoglutarate and its cognate receptor GPR99 in retinal vessel growth.
The retinal expression levels of GPR99 were determined by real-time PCR and western blots. Effects of -ketoglutarate on developmental retinal vascularization were assayed 2 days following intravitreal injection (250µM) of P1, P3 and or P7 Sprague-Dawley rat pups. Areas of central vasobliteration were assessed after intravitreal injection of -ketoglutarate (P5-P7) and the anti-angiogenic effects of SiGPR99 were investigated in the neovascular phase of an oxygen induced model of ROP (80%-10% O2 : 24hrs cycling protocol). Responsiveness of GPR99 to fluctuating O2 levels was determined in vitro by real-time PCR and western blot of mixed retinal cell cultures subjected to hypoxia (5%O2) and angiogenic properties confirmed in aortic ring explants.
-Ketoglutarate significantly enhanced developmental vascular densities by 15-30% at different time points assayed. Similarly, -ketoglutarate reduced oxygen induced central vasobliteration in the rat model of ROP ; likely by preserving the original vascular bed and alleviating the hypoxic stimulus for growth. These pro-angiogenic properties of -ketoglutarate were confirmed by the sprouting observed in aortic ring explants.
Our results disclose a novel pro-angiogenic role for -ketoglutarate and its receptor GPR99. These findings provide additional support for the involvement of metabolite signaling in response to the energy compromise observed in ischemic conditions.
This PDF is available to Subscribers Only