Vascular endothelial growth factor (VEGF) signal transduction through the cell surface receptors, VEGFR1 and VEGFR2, regulates angiogenesis - the growth of new capillaries from pre-existent microvasculature. Soluble VEGF receptor-1 (sVEGFR1), a non-signaling splice variant of VEGFR1, has been postulated to inhibit angiogenic signaling via direct sequestration of VEGF ligands, or dominant-negative heterodimerization with surface VEGFRs. The relative contributions of these two mechanisms to sVEGFR1's purported anti-angiogenic effects in vivo are currently unknown. We previously developed a computational model for predicting the compartmental distributions of VEGF and sVEGFR1 throughout the healthy human body, by simulating the molecular interaction networks of the VEGF ligand-receptor system, as well as intercompartmental macromolecular biotransport processes. In this study, we decipher the dynamic processes that led to our prior prediction that sVEGFR1, through its ligand-trapping mechanism alone, did not demonstrate significant steady-state anti-angiogenic effects. We show that sVEGFR1-facilitated tissue-to-blood shuttling of VEGF accounts for a counter-intuitive and drastic elevation in plasma free VEGF concentrations following both intramuscular and intravascular sVEGFR1 infusion. While increasing intramuscular VEGF production reduces free sVEGFR1 levels through increased VEGF-sVEGFR1 complex formation, we demonstrate a competing and opposite effect in which increased VEGF occupancy of neuropilin-1 (NRP1) and the corresponding reduction in NRP1 availability for internalization of sVEGFR1 counter-intuitively increases free sVEGFR1 levels. In conclusion, dynamic intercompartmental transport processes give rise to our counter-intuitive prediction that VEGF-trapping alone does not account for sVEGFR1's anti-angiogenic potential. sVEGFR1's interactions with cell surface receptors, such as NRP1, are also expected to affect its molecular interplay with VEGF.