Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer

HRMs (hypoxia-responsive miRNAs) are a specific group of microRNAs that are regulated by hypoxia. Recent studies revealed that several HRMs including let-7 family miRNAs were highly induced in response to HIF (hypoxia-inducible factor) stabilization in hypoxia, and they potently participated in angiogenesis by targeting AGO1 (argonaute 1) and upregulating VEGF (vascular endothelial growth factor). Here we constructed a novel computational model of microRNA control of HIF-VEGF pathway in endothelial cells to quantitatively investigate the role of HRMs in modulating the cellular adaptation to hypoxia. The model parameters were optimized and the simulations based on these parameters were validated against several published in vitro experimental data. To advance the mechanistic understanding of oxygen sensing in hypoxia, we demonstrated that the rate of HIF-1α nuclear import substantially influences its stabilization and the formation of HIF-1 transcription factor complex. We described the biological feedback loops involving let-7 and AGO1 in which the impact of external perturbations were minimized; as a pair of master regulators when low oxygen tension was sensed, they coordinated the critical process of VEGF desuppression in a controlled manner. Prompted by the model-motivated discoveries, we proposed and assessed novel pathway-specific therapeutics that modulate angiogenesis by adjusting VEGF synthesis in tumor and ischemic cardiovascular disease. Through simulations that capture the complex interactions between miRNAs and miRNA-processing molecules, this model explores an innovative perspective about the distinctive yet integrated roles of different miRNAs in angiogenesis, and it will help future research to elucidate the dysregulated miRNA profiles found in cancer and various cardiovascular diseases.Author Summary: Cells living in a hypoxic environment secrete signals to stimulate new blood vessel growth, a process termed angiogenesis, to acquire more oxygen and nutrients. Hypoxia-inducible factor 1 (HIF-1) accumulates in hypoxia and expedites the release of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF), a prime inducer of angiogenesis. The intermediate signaling events connecting HIF-1 and VEGF are tightly controlled by microRNAs (miRs), which are endogenous, non-coding RNA molecules and powerful regulators in cancer and cardiovascular disease. Given the importance of angiogenesis in tumor development and post-ischemia reperfusion, it holds great basic research and therapeutic value to investigate how miRs modulate intracellular VEGF synthesis to control angiogenesis in hypoxia. We present a computational model that details the interactions between miRs and other key molecules which make up different hierarchies in HIF-miR-VEGF pathway. Based on simulation analysis, new potential therapies are introduced and tested in silico, from which the strategies that most effectively reduce VEGF synthesis in cancer, or enhance VEGF release in ischemic vascular disease are identified. We conclude that in hypoxia different miRs work consonantly to fine-tune the cellular adaptations; when a master miR alters its expression, dynamics of other miRs vary accordingly which together contribute to aberrant RNA/protein profiles observed in the pathophysiology of multiple diseases.