Abstract
VEGF signaling through VEGFR2 is a central regulator of the angiogenic response. Inhibition of VEGF signaling by the stress-induced matricellular protein TSP1 plays a role in modulating the angiogenic response to VEGF in both health and disease. TSP1 binding to CD47 inhibits VEGFR2 activation. The full implications of this inhibitory interaction are unknown. We developed a detailed rule-based computational model to inquire if TSP1-CD47 signaling through VEGF had downstream effects upon ERK1/2 and calcium. Our Simulations suggest that enhanced degradation of VEGFR2 initiated by the binding of TSP1 to CD47 is sufficient to explain the inhibition of VEGFR2 phosphorylation, calcium elevation, and ERK1/2 activation downstream of VEGF. A complementary mechanism involving the recruitment of phosphatases to the VEGFR2 complex with consequent increase in the rate of receptor dephosphorylation may augment the inhibition of the VEGF signal. The model was then utilized to simulate the effect of inhibiting external TSP1 or the depletion of CD47 as potential therapeutic strategies in restoring VEGF signaling. Results suggest that depleting CD47 is a more efficient strategy in inhibiting the effects of TSP1/CD47 on VEGF signaling. Our results highlight the utility of in silico investigations in elucidating and clarifying molecular mechanisms at the intersection of TSP1 and VEGF biology and in differentiating between competing pro-angiogenic therapeutic strategies relevant to peripheral arterial disease (PAD) and wound healing.
Highlights
VEGF is crucial in normal angiogenesis during embryonic vascular development (Breier et al, 1992; Breier, 2000), wound healing (Bao et al, 2009), and the control of adult vascular permeability and homeostasis (Ku et al, 1993; Lee et al, 2007; Curwen et al, 2008; Lazarus and Keshet, 2011)
CD47 has a binding site for TSP1 and another domain capable of binding and associating with vascular endothelial growth factor receptor type 2 (VEGFR2) there is evidence to suggest that CD47 is associated with signal regulatory protein α [SIRPα and that this interaction maybe important in TSP1 effects in endothelial cells (Yao et al, 2014)
The model incorporated detailed molecular mechanisms using a rule-based model for receptor-receptor interaction and a coarse-grained model for signaling to calcium and ERK1/2 from the activated receptors
Summary
VEGF is crucial in normal angiogenesis during embryonic vascular development (Breier et al, 1992; Breier, 2000), wound healing (Bao et al, 2009), and the control of adult vascular permeability and homeostasis (Ku et al, 1993; Lee et al, 2007; Curwen et al, 2008; Lazarus and Keshet, 2011) Under pathological angiogenesis such as cancer, VEGF is crucial in the development of tumor vasculature and subsequent metastasis (Saharinen et al, 2011). In peripheral arterial disease (PAD), the blood flow to the lower extremities is compromised as a result of TSP1 Inhibition of VEGFR2 Activation atherosclerotic occlusion leading to vascular loss This may partly be attributable to the inhibition of pro-angiogenic signaling and endothelial cell resistance to VEGF (Annex, 2013). Development of antibodies targeting VEGF as well as kinase inhibitors targeting VEGFR2 have been effective in controlling pathological angiogenesis in diseases characterized by abnormal angiogenesis such as age related macular degeneration, diabetes induced macular edema, and cancer (Rosenfeld et al, 2006; Tah et al, 2015; Ferrara and Adamis, 2016)
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