Vascular endothelial growth factor and diabetic complications

Intraocular delivery of anti-vascular endothelial growth factor (VEGF) therapies is now used widely to treat age-related macular degeneration, and is currently undergoing evaluation in clinical trials for treatment of diabetic retinopathy. An important aspect of anti-VEGF treatment is that while the agents are injected into the vitreous cavity, they may be absorbed systemically, thus potentially affecting systemic VEGF levels. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and the soluble form of VEGF-R1 are key to angiogenesis, vasculogenesis, neurogenesis and hemodynamics. These cellular processes are regulated by complicated negative and positive feedback loops, many of which are disrupted and altered in diabetes. The VEGF protein, mRNA, as well as the actual VEGF receptor levels, appear to be impaired in diabetes in microvascular and macrovascular vessel beds. What is not clear is the exact role and influence that these levels have on an organ's function. In some organ systems, elevated VEGF levels act as a pathologic angiogenic stimulus (i.e., ocular neovascularization) whereas in others, low levels of VEGF activity leads to pathology (i.e., cardiomyopathy, wound healing and peripheral neuropathy). Diabetic patients have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Certain intraocular anti-VEGF treatments could therefore have an adverse effect in this population by possibly affecting circulating and organ-specific VEGF and VEGF receptor levels.