The vascular endothelial growth factor (VEGF) family of cytokines is involved in the maintenance of existing adult blood vessels as well as in angiogenesis, the sprouting of new vessels. To study the pro-angiogenic activation of VEGF receptors by VEGF family members in skeletal muscle, we develop a computational model of VEGF isoforms (VEGF₁₂₁, VEGF₁₆₅), their cell surface receptors and the extracellular matrix in in vivo tissue. We build upon our validated model of the biochemical interactions between VEGF isoforms and receptor tyrosine kinases (VEGFR1 and VEGFR2) and non-signaling Neuropilin-1 co-receptors in vitro. The model is general and could be applied to any tissue; here we apply the model to simulate the transport of VEGF isoforms in human vastus lateralis muscle, which is extensively studied in physiological experiments. The simulations predict the distribution of VEGF isoforms in resting (non-exercising) muscle and the activation of VEGF receptor signaling. Little of the VEGF protein in muscle is present as free, unbound extracellular cytokine; the majority is bound to the cell surface receptors or to the extracellular matrix. However, interstitial sequestration of VEGF₁₆₅ does not affect steady-state receptor binding. In the absence of Neuropilin, VEGF₁₂₁ and VEGF₁₆₅ behave similarly, but Neuropilin enhances the binding of VEGF₁₆₅ to VEGFR2. This model is the first to study VEGF tissue distribution and receptor activation in human muscle, and provides a platform for the design and evaluation of therapeutic approaches.