Vascular Endothelial Growth Factor-A (VEGF-A) is an angiogenic agent that drives blood vessel formation in solid tumors and other diseases, such as macular degeneration and diabetic retinopathy. Several therapies that target the ability of VEGF to stimulate angiogenesis have been approved. These therapies regulate VEGF-A activity by binding VEGF-A, thereby blocking VEGF-A from binding to its receptor on target cells. This technology utilizes a different approach to regulating VEGF-A activity by providing a VEGF-A protein antagonist that is produced by engineering native VEGF-A protein. The engineered VEGF-A protein disrupts heparin sulfate proteoglycan binding to the VEGF-A/VEGF receptor complex, an activity that is essential for the angiogenic properties of native VEGF-A. The antagonist has a binding affinity for both FLT-1 (VEGFR-1) and KDR/FLK-1 (VEGFR-2) that is equivalent to that of native VEGF-A and specifically antagonizes all VEGF-A-stimulated signaling events.