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.
Highlights
Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis in physiological and pathophysiological states
A detailed model of VEGF receptor 2 (VEGFR2) signaling to Akt and endothelial nitric oxide synthase (eNOS) was constructed in order to test precise mechanisms of the experimentally observed inhibition of this pathway by TSP1 (Kaur et al, 2010, 2014)
The model predicted that this mechanism did not lead to the inhibition of VEGFR2 phosphorylation, Akt activation, and eNOS phosphorylation on serine 1177 residue (S1177)
Summary
Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis in physiological and pathophysiological states. The response to VEGF is mediated by its binding to multiple receptors and co-receptors on endothelial cells such. VEGF binding to receptor tyrosine kinase VEGFR2 leads to the activation of downstream signaling pathways including ERK1/2 and PI3K/Akt that induce cellular proliferation, survival, motility, and enhanced vascular permeability (Olsson et al, 2006; Dellinger and Brekken, 2011; Simons et al, 2016), the dominant pathway in post-natal angiogenesis. VEGF-VEGFR2 activation induces nitric oxide (NO) release as a result of the activation of endothelial nitric oxide synthase (eNOS), substantially contributing to the angiogenic response (Papapetropoulos et al, 1997; Fukumura et al, 2001)
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