The impact of high density receptor clusters on VEGF signaling

TL;DR

This paper models how high-density VEGF receptor clusters influence signaling by examining receptor localization, clustering, and dimerization through a simplified ODE model, revealing the impact of receptor concentration and ligand availability.

Contribution

It introduces a minimalistic mathematical model to study the effects of receptor clustering on VEGF signaling, highlighting the role of high-density receptor regions in dimerization and signal initiation.

Findings

Receptor clustering affects VEGF receptor dimerization.

High-density receptor regions act as transient traps for receptors.

Model simulations show the influence of receptor concentration and ligand availability on signaling.

Abstract

Vascular endothelial growth factor (VEGF) signaling is involved in the process of blood vessel development and maintenance. Signaling is initiated by binding of the bivalent VEGF ligand to the membrane-bound receptors (VEGFR), which in turn stimulates receptor dimerization. Herein, we discuss experimental evidence that VEGF receptors localize in caveloae and other regions of the plasma membrane, and for other receptors, it has been shown that receptor clustering has an impact on dimerization and thus also on signaling. Overall, receptor clustering is part of a complex ecosystem of interactions and how receptor clustering impacts dimerization is not well understood. To address these questions, we have formulated the simplest possible model. We have postulated the existence of a single high affinity region in the cell membrane, which acts as a transient trap for receptors. We have defined an ODE model by introducing high- and low-density receptor variables and introduce the corresponding reactions from a realistic model of VEGF signal initiation. Finally, we use the model to investigate the relation between the degree of VEGFR concentration, ligand availability, and signaling. In conclusion, our simulation results provide a deeper understanding of the role of receptor clustering in cell signaling.