Computational Systems Biology Modeling of the Angiopoietin‐Tie Signaling Pathway and its Crosstalk with α5β1 Integrin in Endothelial Cells

Abstract

The Angiopoietin (Ang)-Tie signaling pathway is a major signaling pathway regulating vascular growth (angiogenesis), stability, and permeability. Dysregulation in the pathway is known to lead to vascular dysfunction related to many diseases, including cardiovascular diseases, systemic inflammation, diabetic macular edema, and cancer. Integrin α5β1 has been demonstrated to play an important role in regulating Ang-Tie and its downstream signaling. The understanding of the molecular mechanisms of the α5β1/Ang-Tie crosstalk has been limited due to the complexity of the reaction network formed by the ligands, receptors, integrin interactions, and the molecular regulatory mechanisms. The present study uses a mechanistic computational model of the Ang-Tie signaling pathway and its crosstalk with α5β1 to demonstrate the ability of integrin α5β1 to modulate Tie2 activation by affecting the junctional localization of the co-receptor Tie1. The model provides a mechanistic explanation of how AXT107, an α5β1-modulating peptide, promotes the Tie2-activation function of Ang2 and predicts that simultaneously targeting α5β1 and VE-PTP can synergistically enhance the activation of Tie2 in endothelial cells in pathological states. The model is also used to make quantitative prediction of the effects of simultaneously targeting various aspects of the α5β1/Ang-Tie crosstalk, including the integrin, VE-PTP, and Ang2.