TY - JOUR
T1 - Computational modeling of synergistic interaction between αVβ3 integrin and VEGFR2 in endothelial cells
T2 - Implications for the mechanism of action of angiogenesis-modulating integrin-binding peptides
AU - Bazzazi, Hojjat
AU - Zhang, Yu
AU - Jafarnejad, Mohammad
AU - Popel, Aleksander S.
N1 - Funding Information:
This work was supported by the National Institutes of Health grants R01HL101200 , R21EY026148 , and R01CA138264 (ASP). We thank Drs. Kairbaan Hodivala-Dilke, Adam C. Mirando and Niranjan B. Pandey for insightful discussions related to the angiogenesis-modulating integrin-binding peptides.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/10/14
Y1 - 2018/10/14
N2 - Cooperation between VEGFR2 and integrin αVβ3 is critical for neovascularization in wound healing, cardiovascular ischemic diseases, ocular diseases, and tumor angiogenesis. In the present study, we developed a rule-based computational model to investigate the potential mechanism by which the Src-induced integrin association with VEGFR2 enhances VEGFR2 activation. Simulations demonstrated that the main function of integrin is to reduce the degradation of VEGFR2 and hence stabilize the activation signal. In addition, receptor synthesis rate and recruitment from internal compartment were found to be sensitive determinants of the activation state of VEGFR2. The model was then applied to simulate the effect of integrin-binding peptides such as tumstatin and cilengitide on VEGFR2 signaling. Further, computational modeling proposed potential molecular mechanisms for the angiogenesis-modulating activity of other integrin-binding peptides. The model highlights the complexity of the crosstalk between αVβ3 integrin and VEGFR2 and the necessity of utilizing models to elucidate potential mechanisms in angiogenesis-modulating peptide therapy.
AB - Cooperation between VEGFR2 and integrin αVβ3 is critical for neovascularization in wound healing, cardiovascular ischemic diseases, ocular diseases, and tumor angiogenesis. In the present study, we developed a rule-based computational model to investigate the potential mechanism by which the Src-induced integrin association with VEGFR2 enhances VEGFR2 activation. Simulations demonstrated that the main function of integrin is to reduce the degradation of VEGFR2 and hence stabilize the activation signal. In addition, receptor synthesis rate and recruitment from internal compartment were found to be sensitive determinants of the activation state of VEGFR2. The model was then applied to simulate the effect of integrin-binding peptides such as tumstatin and cilengitide on VEGFR2 signaling. Further, computational modeling proposed potential molecular mechanisms for the angiogenesis-modulating activity of other integrin-binding peptides. The model highlights the complexity of the crosstalk between αVβ3 integrin and VEGFR2 and the necessity of utilizing models to elucidate potential mechanisms in angiogenesis-modulating peptide therapy.
KW - Computational model
KW - Integrin signaling
KW - Mathematical model
KW - Systems biology
KW - VEGF
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U2 - 10.1016/j.jtbi.2018.06.029
DO - 10.1016/j.jtbi.2018.06.029
M3 - Article
C2 - 30036530
AN - SCOPUS:85050683354
VL - 455
SP - 212
EP - 221
JO - Journal of Theoretical Biology
JF - Journal of Theoretical Biology
SN - 0022-5193
ER -