The light‐sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid‐rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders.

Breakdown of the blood-retinal barrier (BRB) causes retinal edema and vision loss. We investigated the role of Wnt signaling in maintaining the BRB by limiting transcytosis. Mice lacking either the Wnt co-receptor low-density lipoprotein receptor–related protein 5 (Lrp5−/−) or the Wnt ligand Norrin (Ndpy/−) exhibit increased retinal vascular leakage and enhanced endothelial transcytosis. Wnt signaling directly controls the transcription of an endothelium-specific transcytosis inhibitor, major facilitator superfamily domain–containing protein 2a (MFSD2A), in a β-catenin–dependent manner. MFSD2A overexpression reverses Wnt deficiency–induced transcytosis in endothelial cells and in retinas. Moreover, Wnt signaling mediates MFSD2A-dependent vascular endothelium transcytosis through a caveolin-1 (CAV-1)–positive caveolae pathway. In addition, levels of omega-3 fatty acids are also decreased in Wnt signaling–deficient retinas, reflecting the basic function of MFSD2A as a lipid transporter. Our findings uncovered the Wnt/β-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.

Nerve growth factor (NGF) has been shown to promote survival and function of cholinergic neurons in the basal forebrain in various models of neuronal degeneration in rodents and primates. We examined whether a regulatable in vivo expression system can control the survival of cholinergic neurons after injury, using a tetracycline-regulated promoter ("tet-off" system) to modulate lentiviral NGF gene delivery. Two weeks after lesions to cholinergic neurons, significant cell rescue (65+/-8% neuron survival; P<0.005 compared to controls) was observed when NGF expression was activated. Treatment with the tetracycline analog doxycycline to turn gene expression "off" resulted in a significant loss of cholinergic neurons (only 37+/-5% neurons remained, an amount that did not differ from untreated, lesioned controls). Animals treated with a constitutively active and robust nonregulated NGF expression system showed the same degree of neuronal rescue (73+/-8%) as animals treated with activated tet-regulated vectors. ELISA measurements confirmed that oral treatment of animals with doxycycline reduced NGF protein levels to levels in untreated control subjects. These data demonstrate for the first time that NGF delivery by lentiviral gene transfer using tetracycline-regulated promoters can completely regulate neuronal rescue and protein production in the brain.