Vascular endothelial growth factor (VEGF) is a key promoter of angiogenesis and a major target of pro-angiogenic therapy for peripheral arterial disease (PAD). Greater understanding of VEGF angiogenic signaling and guidance by gradients for new capillaries will aid in developing new pro-angiogenic therapies and improving existing treatments. However, in vivo measurements of VEGF concentration gradients at the cell scale are currently impossible. We have developed a computational model to quantify VEGF distribution in extensor digitorum longus skeletal muscle using measurements of VEGF, VEGF receptor (VEGFR), and neuropilin-1 (NRP1) expression in an experimental model of rat PAD. VEGF is secreted by myocytes, diffuses through and interacts with extracellular matrix and basement membranes, and binds VEGFRs and NRP1 on endothelial cell surfaces of blood vessels. We simulate the effects of increased NRP1 expression and of therapeutic exercise-training on VEGF gradients, receptor signaling and angiogenesis. Our study predicts that angiogenic therapy for PAD may be achieved not only through VEGF upregulation, but also through modulation of VEGFRs and NRP1. We predict that: expression of 10⁴ NRP1/cell can increase VEGF binding to receptors by 1.7-fold (versus no NRP1); in non-exercise-trained muscle with PAD, angiogenesis is hindered due to limited VEGF upregulation, signaling and gradients; in exercise-trained muscle, VEGF signaling is enhanced by upregulation of VEGFRs and NRP1, and VEGF signaling is strongest within the first week of exercise therapy; and that hypoxia-induced VEGF release is important to direct angiogenesis towards unperfused tissue.