VEGF-Extracellular Matrix Interactions in Choroidal Neovascularization
Excess vascular endothelial growth factor (VEGF), a protein that stimulates blood vessel growth, has been shown to be a major cause of unwanted vessel growth into the retina in wet age-related macular degeneration (AMD). Dr. Matthew Nugent and colleagues propose to identify new ways that VEGF activity is naturally controlled by interactions with the protein fibronectin, so that this pathway can be targeted for a more effective treatment for wet AMD.
Dr. Matthew Nugent and colleagues are seeking to determine if a new biochemical process that they have discovered plays a critical role in causing the abnormal growth of blood vessels into the retina in wet AMD. VEGF is increased in wet AMD, and inhibitors of VEGF have been shown to be somewhat effective in treating this disease. Nugent recently discovered that a complex sugar called heparan sulfate, when made by cells grown in low oxygen, can modify the association of VEGF with a protein called fibronectin, which is part of the surrounding cell-support meshwork. Preliminary data indicate that VEGF becomes activated upon association with fibronectin by presenting it to its binding partners and protecting it from natural inhibitors. This may lead to enhanced recruitment of blood vessel cells. Current therapies are designed to bind free VEGF or VEGF partners to inhibit the activity. Thus, VEGF associated with fibronectin may be shielded from these therapies, which may be part of the reason that current treatments are only partially effective.
Nugent's project aims to explore how this new process (VEGF binding to fibronectin) may cause abnormal blood vessel growth and to determine if targeting this new interaction may fully inhibit growth beyond that observed with current therapies. Furthermore, the idea that heparan sulfate may control this process is novel and may represent a newly discovered biological mechanism that tissues use to locally control the activity of potent factors such as VEGF. At the end of this study, Nugent will have a better understanding of the structure and activity requirements for heparan sulfate to modify fibronectin, which will provide insight into designing new complex sugars to antagonize this process.