Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer
Fig 8
Sensitivity analysis of key species in the pathway.
Sensitivity of (A) cytoplasmic HIF1-α, (B) free form AGO1, (C) free form let-7, and (D) VEGF to variations in different sets of kinetic parameters (direct production and degradation rates excluded). (A-D) Kf(X/Y) stands for the forward reaction constant of species X binding species Y; Vm(X) stands for the speed of reaction X; Kf(X) stands for the forward rate constant of species X dissociation. Detailed description of each parameter is available in the supplemental information. (E) At different O2 levels, TTP mRNA overexpression is tested as an anti-angiogenic therapy in silico compared to miR-based therapeutic strategies. (F) Affinity of O2 binding with PHD2 or FIH and HIF-1α translocation rate contribute to the trend of HIF-1α stabilization in hypoxia. (G) Relative downregulation of AGO1 in hypoxia is influenced by its binding with let-7. (F-G) Parameters are set to 500% of their original values in the comparisons. For each new value, steady state levels of all species, after the model is simulated in normoxia for a long time span, are collected and considered a new set of initial conditions. HIF-1α and AGO1 levels in hypoxia are normalized with respect to their concentrations at time zero (normoxic steady states).