The development of blood vessels is a part of normal growth in almost all tissues. But it can also be pathological: Many eye conditions leading to blindness involve abnormal blood vessel formation, including retinopathy of prematurity in infants, diabetic retinopathy and wet, age-related macular degeneration (AMD).
Blood vessels produced under stress conditions such as inflammation or low oxygen, especially in the retina, are apt to be poorly constructed and leaky. Vascular endothelial growth factor, or VEGF, has been shown to contribute to pathologic vessel growth, and anti-VEGF treatments are now widely used to control the overproliferation of blood vessels, such as Lucentis for wet macular degeneration.
Unfortunately, VEGF-binding antibodies can block not just excess VEGF but the baseline normal amount needed for vessels and neighboring neurons to survive, with potentially serious side effects. “The use of anti-VEGF antibodies is very powerful, but it’s also worrisome, particularly in the case of retinopathy of prematurity, because it leaks into the systemic circulation and suppresses blood vessel development in the brain, the gut and the entire body,” says Lois Smith, MD, PhD, a professor of ophthalmology at Boston Children’s Hospital and Harvard Medical School.
A recent study led by Smith brings medicine closer to a safer treatment.
Smith’s team examined how blood vessels interact with neighboring neurons to learn why and how excess VEGF is produced — akin to learning more about a person by studying her relationships.
Blood vessels, neurons and glia (non-neuronal cells with varied roles in the nervous system) form a complex communication system to support central nervous system tissues, including the retina. Cytokines, proteins important in cell signaling, are thought to be important in this crosstalk.
Studying the mouse retina, Smith, with Ye Sun, PhD, and other colleagues at Boston Children’s, looked at one protein called SOCS3 (suppressor of cytokine signaling-3), known to be produced by neurons and glial cells and known to curb the inflammation that triggers VEGF production. The team found that mice that develop retinopathy under reduced oxygen conditions produce large amounts of SOCS3 in their retinas.
Could SOCS3 be the key in controlling excess VEGF production? To find out, Sun et al. deleted the SOCS3 gene in the neurons of mouse retinas. They raised the mice in an oxygen chamber for a period, then moved the mice to relatively low-oxygen room air, simulating conditions that cause retinopathy in premature infants in incubators.
Without SOCS3, the mice produced more VEGF in their retinas, suggesting that SOCS3 prevents neurons and glial cells from releasing too much VEGF. When SOCS3 production was highly induced, VEGF production was suppressed.
The researchers believe that targeting SOCS3 offers the possibility of simply adjusting VEGF levels rather than blocking all VEGF, allowing more intelligent control of pathologic vessel growth and a better way to prevent retinopathy and blindness. Future research, says Smith, could test a gene-therapy approach, using adeno-associated virus to deliver SOCS3 in neuronal and glial cells to effectively modulate rather than suppress VEGF.
Smith and Sun discuss the implications of their work in this podcast.
Jane Patrick is a science writer in Boston Children’s Department of Ophthalmology.
Source: Ye Sun, Meihua Ju, Zhiqiang Lin, Thomas W. Fredrick, Lucy P. Evans, Katherine T. Tian, Nicholas J. Saba, Peyton C. Morss, William T. Pu, Jing Chen, Andreas Stahl, Jean-Sébastien Joyal, Lois E. H. Smith. SOCS3 in retinal neurons and glial cells suppresses VEGF signaling to prevent pathological neovascular growth. Sci Signal 2015 Sept 22; doi: 10.1126/scisignal.aaa8695.