A mechanistic computational model of the HIF signaling pathway in endothelial cells

In conditions such as cancer, cardiovascular diseases, and retinal diseases, cells under hypoxia activate oxygen-sensing mechanisms, promoting adaptation and survival. Many hypoxia computational models predate standardized identifiability analyses and lack systematic treatment of the HIF isoform-specific dynamics in endothelial cells. We present a technically validated mechanistic model of the HIF pathway in endothelial cells, capturing graded oxygen sensitivity and the transition from HIF1α-dominated acute to HIF2α-dominated prolonged hypoxic responses. Following identifiability analyses, the model was calibrated and validated against independent datasets, achieving Pearson correlations of 0.7-0.95 and no systematic residual bias (Runs test p ≥ 0.35). Simulations revealed dose-dependent HIF stabilization and VEGFA mRNA induction, a time-dependent shift in transcriptional control from HIF1α to HIF2α, and non-redundant isoform-specific effects of PHD2 and PHD3 inhibition. This validated model provides a robust mechanistic framework for studying endothelial hypoxia signaling, suitable for integration into larger computational models of ischemic disease.