Neuronal energy demands are met by a tightly coupled and adaptive vascular network that supplies nutrients and oxygen. The retina is one of the highest energy-consuming organs, exceeding the metabolic rate of the brain; blood vessels grow and regress in reaction to changes in these high demands (Ames et al., 1992b, Anderson and Saltzman, 1964, Yu and Cringle, 2001). Reduced nutrients and reduced oxygen availability instigate compensatory albeit misguided pathological neovascularization in proliferative retinopathies (Chen and Smith, 2007, Sapieha et al., 2010). Conversely, impaired retinal ganglion cell (RGC) and photoreceptor survival are correlated with abrogated vascular development (Pennesi et al., 2008) and as neurons degenerate, the retinal vasculature atrophies to match the reduced metabolic requirements (Wang et al., 2000). In mice, genetic ablation of retinal ganglion cell neurons suppresses the inner retinal vascular development (Sapieha et al., 2008). Ablation of amacrine interneurons also prevents the development of the intermediate vascular plexus (Usui et al., 2015), while photoreceptor degeneration is associated with thinning of the choroid and inner retinal blood vessels (Ayton et al., 2013, Dhoot et al., 2013, Toto et al., 2016). Thinning of the choriocapillaris, in turn, may exacerbate retinal degeneration (Bird, 2010, Whitmore et al., 2015). However, the specific mediators that link neuronal metabolism with retinal angiogenesis in the developing eye and retinal disease remain largely unknown. Conditions such as diabetic retinopathy, vaso-proliferative retinopathy of prematurity and neovascular age-related macular degeneration (AMD) have been characterized as diseases of the vasculature. However, it is becoming more evident that the metabolic needs of the neural retina profoundly influence blood vessel supply in development and in disease.

Retinal oxygen sources and the vaso-proliferative response to low oxygen levels have been well characterized. However, understanding the specific fuels used in the retina to generate ATP and supply building blocks for biosynthesis, as well as understanding the vaso-proliferative response to the lack of fuel are also key to neurovascular development. The metabolic and energy needs of the retina have been assumed to be met by glucose, as the retina is part of the CNS, and the brain relies almost exclusively on glucose (Mergenthaler et al., 2013). There are two primary pathways that cells can use to generate ATP from glucose, glycolysis and oxidative phosphorylation. However, Cohen and Noell concluded in 1960 that a substantial portion of the energy produced through oxidation by the retina (around 65%) was not derived from glucose (Cohen and Noell, 1960). We recently showed that the retina (photoreceptors) can also oxidize lipid through fatty acid β-oxidation to produce ATP, accounting for the energy gap noted by Cohen (Joyal et al., 2016). Little is known about lipid versus glucose fuel substrate preference and its importance during retinal development and pathology. Here we review the neuronal energy demands of the retina, describing both glucose and lipid metabolism as forces that shape the vascular supply of the eye in development and in vaso-proliferative eye diseases.