Boston, Mass. — Scientists at Schepens Eye Research Institute, a subsidiary of Mass. Eye and Ear and affiliate of Harvard Medical School, have discovered that VEGF (vascular endothelial growth factor), which is known to cause blood vessel growth, has a separate function. According to their study, VEGF seems to unexpectedly bind the receptor for another growth factor known as platelet-derived growth factor (PDGF), and thereby prevent PDGF from binding. This discovery suggests that VEGF may contribute to the development of proliferative vitreoretinopathy (PVR), the most common serious side-effect of retinal re-attachment surgery. In PVR, an abnormal membrane forms on the surface of the newly re-attached retina and then proceeds to contract, which cause a secondary detachment.
This finding, published in the May issue of Molecular and Cellular Biology, is significant for two reasons, according to Dr. Andrius Kazlauskas, a Schepens senior scientist and principal investigator of the study. “First because it may ultimately give us a much-needed targets for drugs to prevent PVR, which has no treatment except another re-attachment surgery that often fails, causing severe vision loss. And second, because this unusual relationship of growth factors might also be occurring in other disorders.”
Growth factors are proteins that stimulate the migration and proliferation of cells by binding to receptors on those cells, usually receptors specifically designated for the individual growth factor. In the case of PVR, there is strong evidence that growth factors in vitreous activate the PDGF receptor and thereby drive the abnormal membrane formation on the retina after retinal re-attachment surgery.
Each year, nearly 10 percent of the 40,000 Americans who undergo retinal re-attachment surgery develop PVR. While the cause is not well understood, scientists believe it may involve displaced cells from the back of the eye (released during the surgery or the original trauma) that become stimulated to organize into a destructive membrane by growth factors in the vitreous, the clear gel that fills the space between the retina at the back of the eye and the lens at the front of the eye.
In fact, previous research has shown that when PVR is present, the amount of a handful of growth factors in vitreous increases. Furthermore, cells in the PVR membrane express the PDGFR, which is activated by the vitreal growth factors and thereby stimulates cell proliferation, migration and the forming of cell matrixes.
“However, the mystery has been that the PDGFs don’t seem to be binding very often or well with these receptors. When they do bind, the receptors self-destruct rather than activating the growth of the membrane characteristic of PVR, says Kazlauskas. “We decided there must be something else binding to these receptors that could be contributing to the formation of the PVR membrane.”
Kazlauskas and his team decided to find out what. Through a series of experiments they discovered that when vitreous was present, PDGFs’ ability to bind their “own” receptors was impaired. This finding suggested that vitreous from patients with PVR contained an agent that prevented PDGFs from binding to the receptor. The experiment that followed revealed that this was indeed the case, and that VEGF was the agent in vitreous that prevented PDGFs from binding their receptor.
This observation lit several light bulbs, according to Kazlauskas. “First it confirmed previous studies showing that VEGF and PDGF were structurally very similar. Furthermore, the new findings extended the relevance of the PDGF/VEGF relationship to a blinding eye disease.
“Second, it strengthened our emerging suspicion regarding which growth factors in vitreous of patients in PVR are the ones that drive this disease. Finally, it made us think about a new way to prevent PVR, i.e. by neutralizing VEGF,” he says.
He adds, “This is particularly exciting because there already are safe and effective approaches to block VEGF, which have never been considered for PVR because they didn’t make sense without understanding the relationship among the vitreal growth factors that came to light in the course of this study.”
So the implications are promising. “By measuring the level of VEGF in the vitreous before surgery, we may be able to predict the likelihood of PVR happening for a specific individual,” says Kazlauskas.
“And, of course, the real hope is that anti-VEGF drugs or compounds might someday be able to prevent the disease altogether, eliminating the fear of this complication for patients,” he adds.
According to Kazlauskas, the next steps for him and his team will involve investigating the impact of anti-VEGF compounds to see if they can actually prevent or arrest the development of PVR.”
Steven Pennock, PhD, at Schepens Eye Research Institute, was the first author of the study, which is titled Vascular Endothelial Growth Factor A Competitively Inhibits Platelet- Derived Growth Factor (PDGF)-Dependent Activation of PDGF Receptor and Subsequent Signaling Events and Cellular Responses.
About Mass. Eye and Ear: Founded in 1824, Massachusetts Eye and Ear is an independent specialty hospital providing patient care for disorders of the eye, ear, nose, throat, head and neck. Mass. Eye and Ear is an international leader in Ophthalmology and Otolaryngology research and a teaching partner of Harvard Medical School. The Massachusetts Eye and Ear and Schepens Eye Research Institute united in 2010 to form the world’s largest and most robust private basic and clinical ophthalmology research enterprise. For more information about Mass. Eye and Ear, call 617-523-7900 or visit www.MassEyeAndEar.org.