Project 461639

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 nutrient and oxygen delivery, leading to visual impairment. Finding ways to regenerate blood vessels rapidly may help improve vision. Low oxygen delivery is considered the primary driver of new blood vessel growth. In mice, retinal vessels stop growing and degenerate upon exposure to high oxygen concentration. Soon after that initial insult, however, new vessels paradoxically begin to revascularize damaged regions of the retina, despite excessive tissue oxygen still present; this suggests the presence of oxygen-independent drivers of vessel growth. Nutrients fuel the energy requirements of the retina. We, therefore, hypothesize that fuel deficiency may promote 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 is then 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 targeted to discover new therapies to improve vision in retinopathies.