Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer
Fig 7
Simulations of potential pathway-related therapeutic strategies in tumor and PAD.
Different doses of (A) let-7 antagonists, (B) AGO1 mRNA overexpression, and (C) miR-15a mimics are applied and total VEGF production curves at different O2 tensions are obtained. (D) Either antagonizing let-7 or overexpressing AGO1 strongly suppresses VEGF synthesis compared to the control curve, particularly in severely hypoxic conditions (0–2% O2) that simulate in vivo tumor oxygenation. More specifically, let-7 antagonist is more effective because it maintains a stable and higher intracellular AGO1 expression than direct AGO1 overexpression. Since both AGO1 and Dicer are significantly reduced in hypoxia and are limiting factors in miR maturation and stabilization, the response of miR-15a overexpression is relatively insignificant. The results should be evaluated qualitatively since many proteins could have much lower concentration in vivo compared to in vitro cultures which might invalidate some of the model assumptions. (E-F) Testing the impact of different doses of let-7 mimics and miR-15a antagonists on VEGF release in PAD conditions, which is modeled as a weak let-7 induction by HIF-1 in hypoxia (see Methods for details). Antagonizing miR-15a, compared to overexpressing let-7, results in stronger promotion on VEGF production. (G) The combination of miR-15a antagonist with let-7 mimic positively modulates angiogenesis; it elevates VEGF production by more than two fold with respect to PAD controls in hypoxia.