A computational analysis of in vivo VEGFR activation by multiple co-expressed ligands
(A) One at a time, each baseline ligand secretion or receptor production rate (inputs- listed across the top), was increased by 2%, then decreased by 2%. For each perturbation, the change in plasma ligand and EC surface receptor levels (outputs- listed on the left) in in both the main body mass (“Body”) and calf muscle (“Calf”) were obtained. The average change in output from baseline levels was calculated, and divided by the change in input (+/-2%) to give the relative change in output per % change in input. (B) Schematic of positive feedback in VEGF gene and protein levels in the model. An increase in VEGF expression increases local VEGF protein, increasing VEGF binding to VEGFR2, and subsequent internalization and degradation. This decreases total VEGFR2 protein levels, leading to reduced VEGF-VEGFR2 complex formation, which reduces net endothelial consumption of VEGF protein. To accommodate, in the model, VEGFR2 expression was increased until target baseline levels were achieved for all ligands and receptors. A similar positive feedback loop exists for changes in VEGFR2 expression.