Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model

Abstract

Hypoxia is an important physiological stress signal that drives angiogenesis, the formation of new blood vessels. Besides an increase in the production of pro-angiogenic signals such as vascular endothelial growth factor (VEGF), hypoxia also stimulates the production of anti-angiogenic signals. Thrombospondin-1 (TSP-1) is one of the anti-angiogenic factors whose synthesis is driven by hypoxia. Cellular synthesis of TSP-1 is tightly regulated by different intermediate biomolecules including proteins that interact with hypoxia-inducible factors (HIFs), transcription factors that are activated by receptor and intracellular signaling, and microRNAs which are small non-coding RNA molecules that function in post-transcriptional modification of gene expression. Here we present a computational model that describes the mechanistic interactions between intracellular biomolecules and cooperation between signaling pathways that together make up the complex network of TSP-1 regulation both at the transcriptional and post-transcriptional level. Assisted by the model, we conduct in silico experiments to compare the efficacy of different therapeutic strategies designed to modulate TSP-1 synthesis in conditions that simulate tumor and peripheral arterial disease microenvironment. We conclude that TSP-1 production in endothelial cells depends on not only the availability of certain growth factors but also the fine-tuned signaling cascades that are initiated by hypoxia.

Computer Simulation of TSP1 Inhibition of VEGF–Akt–eNOS: An Angiogenesis Triple Threat

“…Thus, the pro-survival action of TSP1–CD47 inhibition might be a more significant outcome than rescuing signals through VEGF. The computational model may be enhanced by incorporating mechanisms that control TSP1 expression [such as miroRNAs as modeled in Zhao et al (2017) ] which would enable investigation of different targeting strategies in combination with what we have already included here. However, in the absence of more clarifying data, our proof-of-concept simulations point at clear distinctions between multiple strategies for rescuing VEGF signaling by blocking TSP1–CD47 axis.…”

TSP‐1 is downregulated and inversely correlates with miR‐449c expression in Cushing's disease

“…However, the decreased expression of TSP‐1 and its cause in Cushing's disease remains to be elucidated. TSP‐1 is proposed to influence the vascular endothelial growth factor (VEGF) pathway by binding to a high‐affinity receptor CD47 and disrupting its association with VEGF receptor 2, which in turn downregulates the pro‐angiogenic signals downstream of VEGF . Ki67, VEGF and matrix metalloproteinase‐9 (MMP9) are among the markers normally used to identify the biochemical characteristics of Cushing's disease …”

Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases

“…MicroRNA-based therapies were simulated under different stimuli conditions that mimicked the dysregulated cytokine environment in diseases to compare the time-course expression levels of myogenic (e.g., MyoD) and OA biomarkers (e.g., aggrecan and collagen 2) [59,60]. Using models of hypoxia, which is regarded as an essential feature in ischemic vascular disease and cancer [78], Zhao et al [66,67] described in detail the complex signal transduction events during hypoxia-driven production of two key angiogenesis regulators (VEGF and TSP-1) [79]. The authors explicitly modeled the participation of several miRs in this process since they target key nodes in the model and their functions are dynamically regulated, both directly and indirectly, by low oxygen tension.…”