(350g) Tuning the Binding Kinetics of Angiogenic Factors for Revascularization Therapies

One common type of ischemic disease is Peripheral Arterial Disease (PAD), which affects nearly 10 million Americans every year.  PAD results from the lack of blood supply to the peripheral tissues, typically caused by a blockage of in a peripheral artery.  One promising approach to treat PAD involves the growth of new blood vessels from existing blood vessels in the body, termed as angiogenesis, to restore blood flow to the peripheral tissue.  A variety of angiogenic growth factors including vascular endothelial growth factor (VEGF), have been extensively studied and shown to play crucial roles in the growth of new blood vessels.  VEGF, along with other growth factors, stimulate an angiogenic response through their interaction with endothelial cell surface receptors on endothelial cells and subsequently causing a signaling cascade.  Clinically, it is typical to extend the stimulatory effect of VEGF with its dose and duration of administration, but this approach often triggers several side-effects. 

This study presents a new way to tune the efficacy of VEGF signaling at a given dose, by controlling binding kinetics of VEGF to cellular receptors.  We hypothesized that a molecule which can bind with cellular integrins and growth factors will greatly improve the efficacy of VEGF to stimulating blood vessel formation.  We examined this hypothesis using natural polymers (e.g., fibronectin and fibronectin fragments) and a fibronectin-mimicking synthetically-modified polymer, alginate.  Interestingly, the co-administration of VEGF with the fibronectin molecules significantly increased the phosphorylation of cellular receptors.  The role in mediating the increase in VEGF receptor activation was further related to the increased association between the VEGF and the fibronectin molecules and the cell’s surface.  Finally, the interaction of these molecules led to both improvements in blood vessel formation in vitro, using an angiogenesis assay, and in vivo, using a mouse model.  Overall, this strategy will not only enhance efficacy of vascular medicine but also be readily extended to a wide array of molecular therapies.