A New Regulator of Retinal Angiogenesis Discovered

Blood vessel growth (angiogenesis) has been shown to be an important factor in diseases from diabetes to cancer. Understanding how the process is regulated, especially in the brain and retina, may yield new treatments for many eye and other central nervous system diseases.

Funded by a Stein Innovation Award “from Research to Prevent Blindness (RPB), David Antonetti, Ph.D., is advancing a novel hypothesis that sheds new and important light on neural-angiogenesis.

When looking for genes uniquely expressed in the blood vessels of the retina and brain, Dr. Antonetti and post-doctoral research fellow Andreia Goncalves, Ph.D., were intrigued to find FLVCR2. A mutated form of FLVCR2 is known to drive the development of Fowler Syndrome, a rare and deadly prenatal disorder that halts the growth of blood vessels but only those in the brain and the retina, with no impact on angiogenesis elsewhere in the embryo.

Since the FLCVR2 gene codes for a transporter of heme, Drs. Antonetti and Goncalves employed various gene editing and analysis tools in cell culture and animal models to explore a novel hypothesis: that heme contributes to the control of blood vessel growth.

Heme is recognized primarily as a component of hemoglobin in red blood cells that carry oxygen. However, heme also contributes to a wide range of functions in other cells, including the regulation of gene expression and the production of energy by mitochondria.

Studies performed by Dr. Goncalves revealed that by reducing heme content in retinal endothelial cells, the blood vessel cells grew markedly faster. By adding heme back to the cells, this process was reversed.

“These and additional studies provide strong evidence that a variation in heme content in retinal and brain endothelial cells acts like a rheostat,” explains Antonetti, “signaling blood vessels whether, how, and how much to grow.”

Further studies are planned in the Antonetti lab to explore the link between FLVCR2, endothelial heme content and brain/ retinal angiogenesis. This has the potential to profoundly impact the identification and development of new therapeutic targets for a number of blinding eye diseases and neurological disorders.