Computer simulation of TSP1 inhibition of VEGF-Akt-eNOS: An angiogenesis triple threat

Hojjat Bazzazi, Yu Zhang, Mohammad Jafarnejad, Jeffrey S. Isenberg, Brian H. Annex, Aleksander S. Popel

Research output: Contribution to journalArticle

Abstract

The matricellular protein thrombospondin-1 (TSP1) is a potent inhibitor of angiogenesis. Specifically, TSP1 has been experimentally shown to inhibit signaling downstream of vascular endothelial growth factor (VEGF). The molecular mechanism of this inhibition is not entirely clear. We developed a detailed computational model of VEGF signaling to Akt-endothelial nitric oxide synthase (eNOS) to investigate the quantitative molecular mechanism of TSP1 inhibition. The model demonstrated that TSP1 acceleration of VEGFR2 degradation is sufficient to explain the inhibition of VEGFR2 and eNOS phosphorylation. However, Akt inhibition requires TSP1-induced phosphatase recruitment to VEGFR2. The model was then utilized to test various strategies for the rescue of VEGF signaling to Akt and eNOS. Inhibiting TSP1 was predicted to be not as effective as CD47 depletion in rescuing signaling to Akt. The model further predicts that combination strategy involving depletion of CD47 and inhibition of TSP1 binding to CD47 is necessary for effective recovery of signaling to eNOS. In all, computational modeling offers insight to molecular mechanisms involving TSP1 interaction with VEGF signaling and provides strategies for rescuing angiogenesis by targeting TSP1-CD47 axis.

Fingerprint

Thrombospondin 1
Nitric Oxide Synthase Type III
Computer Simulation
Vascular Endothelial Growth Factor A
Angiogenesis Inhibitors
Phosphoric Monoester Hydrolases
Phosphorylation

Keywords

  • CD47
  • Computational modeling
  • Systems biology
  • Systems pharmacology
  • TSP1
  • VEGFR2

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Bazzazi, H., Zhang, Y., Jafarnejad, M., Isenberg, J. S., Annex, B. H., & Popel, A. S. (2018). Computer simulation of TSP1 inhibition of VEGF-Akt-eNOS: An angiogenesis triple threat. Frontiers in Physiology, 9(MAY), [644]. https://doi.org/10.3389/fphys.2018.00644

Computer simulation of TSP1 inhibition of VEGF-Akt-eNOS : An angiogenesis triple threat. / Bazzazi, Hojjat; Zhang, Yu; Jafarnejad, Mohammad; Isenberg, Jeffrey S.; Annex, Brian H.; Popel, Aleksander S.

In: Frontiers in Physiology, Vol. 9, No. MAY, 644, 30.05.2018.

Research output: Contribution to journalArticle

Bazzazi, H, Zhang, Y, Jafarnejad, M, Isenberg, JS, Annex, BH & Popel, AS 2018, 'Computer simulation of TSP1 inhibition of VEGF-Akt-eNOS: An angiogenesis triple threat', Frontiers in Physiology, vol. 9, no. MAY, 644. https://doi.org/10.3389/fphys.2018.00644
Bazzazi, Hojjat ; Zhang, Yu ; Jafarnejad, Mohammad ; Isenberg, Jeffrey S. ; Annex, Brian H. ; Popel, Aleksander S. / Computer simulation of TSP1 inhibition of VEGF-Akt-eNOS : An angiogenesis triple threat. In: Frontiers in Physiology. 2018 ; Vol. 9, No. MAY.
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