Abstract
The Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.
Highlights
The Angiopoietin (Ang)-Tie signaling pathway is a major endothelial signaling pathway regulating vascular quiescence, permeability, stability, and growth[1,2]
The present study aims to extend the computational model for the Ang–Tie interaction at the endothelial cell surface[52] to include junctional localization, homo- and heteromeric receptor interactions, and downstream Ang–Tie signaling to quantitatively investigate the molecular mechanisms for Tie1’s role, the context-dependence of Ang2’s agonist activity, and their implications for downstream signaling
Values of parameters, reaction rules in BioNetGen Language (BNGL) and Systems Biology Markup Language (SBML) computer code are available in the Supplementary files
Summary
The Angiopoietin (Ang)-Tie signaling pathway is a major endothelial signaling pathway regulating vascular quiescence, permeability, stability, and growth[1,2]. The Ang–Tie signaling pathway consists of multiple ligands, receptors, and molecular regulators, and mechanisms that form a complex reaction network. The Ang family of ligands consists of. Ang[1] is the natural agonist of Tie[2], and it is associated with vascular growth and stability[14,15]. Ang[2] is primarily considered to be an antagonist of Tie[2] and is mostly associated with vascular leakage and inflammation, it acts as a context-dependent Tie[2] agonist[16,17,18,19,20,21]. Multimeric ligands Ang[1] and
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