Project 455948

Retinopathy of prematurity is one of the leading causes of blindness in children. Loss of blood vessels in the immature retina of premature infants decreases energy delivery to neurons, leading to visual impairment. Finding ways to regenerate blood vessels rapidly may help improve vision. In humans and mice, retinal vessels stop growing and degenerate upon exposure to high oxygen concentration. Soon after that initial insult, however, new blood vessels begin to regenerate. Both healthy and diseased (tufts) vessels form simultaneously to reinstate fuel delivery to retinal neurons. What drives the formation of healthy and diseased vessels remains ill-understood. Nutrients and oxygen fuel the energy requirements of the retina. We, therefore, hypothesize that a change in energy signals may dictate healthy vessel growth to reinstate nutrient supply. Our preliminary findings suggest that Sirtuin-3 (SIRT3), a key regulator of energy signals in mitochondria, governs how blood vessels use various fuels. New blood vessels regenerate faster in Sirt3-deficient mice because glucose becomes the preferred nutrient, conferring growth advantage. Hence, changes in energy metabolism in mitochondria may trigger a regenerative vascular signal. Sirtuin-3, through changes in metabolism, sculpts the vasculature to ensure adequate nutrient supply to the retina. Energy signals may, therefore, also drive angiogenesis, besides oxygen, and are promising targets to discover new therapies that will improve vision for patients with retinopathies.