Abstract
Vascular endothelial growth factor (VEGF) is a powerful regulator of neovascularization. VEGF binding to its cognate receptor, VEGFR2, activates a number of signaling pathways including ERK1/2. Activation of ERK1/2 is experimentally shown to involve sphingosine kinase 1 (SphK1) activation and its calcium-dependent translocation downstream of ERK1/2. Here we construct a rule-based computational model of signaling downstream of VEGFR2, by including SphK1 and calcium positive feedback mechanisms, and investigate their consequences on ERK1/2 activation. The model predicts the existence of VEGF threshold in ERK1/2 activation that can be continuously tuned by cellular concentrations of SphK1 and sphingosine 1 phosphate (S1P). The computer model also predicts powerful effects of perturbations in plasma and ER calcium pump rates and the current through the CRAC channels on ERK1/2 activation dynamics, highlighting the critical role of intracellular calcium in shaping the pERK1/2 signal. The model is then utilized to simulate anti-angiogenic therapeutic interventions targeting VEGFR2-ERK1/2 axis. Simulations indicate that monotherapies that exclusively target VEGFR2 phosphorylation, VEGF, or VEGFR2 are ineffective in shutting down signaling to ERK1/2. By simulating therapeutic strategies that target multiple nodes of the pathway such as Raf and SphK1, we conclude that combination therapy should be much more effective in blocking VEGF signaling to EKR1/2. The model has important implications for interventions that target signaling pathways in angiogenesis relevant to cancer, vascular diseases, and wound healing.
Highlights
Angiogenesis is the growth of new capillaries from the pre-existing vasculature
Computational model of Vascular endothelial growth factor (VEGF) mediated sphingosine kinase 1 (SphK1) and calcium dependent ERK1 and 2 (ERK1/2) activation this study, we have developed a novel computer model for the activation of ERK1/2 and calcium downstream of VEGF receptor type 2 (VEGFR2)
Our model is the first of its kind to incorporate and investigate the consequences of calcium elevation and the role of a cellular lipid modifier known as sphingosine kinase 1 (SphK1)
Summary
Angiogenesis is the growth of new capillaries from the pre-existing vasculature. The process of angiogenesis involves increased proliferation, survival, and migration of the endothelial cells that form the foundation of a developing vascular bed [1]. Formed tumor vasculature contributes to the process of metastasis by shedding tumor cells into the bloodstream that travel throughout the body and provide seeds for new tumors in more distant tissues [4,5] In diseases such as age-related macular degeneration and diabetic macular edema, angiogenesis contributes to the neovascularization of the retina and the leakiness of the ocular blood vessels that may eventually lead to blindness [6]. In other diseases such as peripheral arterial disease, the opposite occurs where the blood capillaries and vessels regress leading to the reduction and, in some cases, total cessation of the blood flow to lower extremities [7]. This condition may require amputation of the regions affected by the lack of blood flow
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