Multi-physics interactions drive VEGFR2 relocation on endothelial cells

Abstract

Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) is a pro-angiogenic receptor, expressed on endothelial cells (ECs). Although biochemical pathways that follow the VEGFR2 activation are well established, knowledge about the dynamics of receptors on the plasma membrane remains limited. Ligand stimulation induces the polarization of ECs and the relocation of VEGFR2, either in cell protrusions or in the basal aspect in cells plated on ligand-enriched extracellular matrix (ECM). We develop a mathematical model in order to simulate the relocation of VEGFR2 on the cell membrane during the mechanical adhesion of cells onto a ligand-enriched substrate. Co-designing the in vitro experiments with the simulations allows identifying three phases of the receptor dynamics, which are controlled respectively by the high chemical reaction rate, by the mechanical deformation rate, and by the diffusion of free receptors on the membrane. The identification of the laws that regulate receptor polarization opens new perspectives toward developing innovative anti-angiogenic strategies through the modulation of EC activation.

A coupled model of transport-reaction-mechanics with trapping. Part I – Small strain analysis

“…VEGFR2 is recruited by VEGFR2-ligands, which are immobilized on the substrate. Accordingly, the complex that is chemically formed is immobile as well and only a model with "trapping" was able to explain the experimental observation published in [70], which cannot be modeled using conventional treatments. support.…”

“…The framework illustrated here has been recently used in [70], showing that multi-physics interactions drive Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) relocation on endothelial cells. The relocation of VEGFR2 on the cell membrane during its adhesion to ligand-enriched extra-cellular matrix was described accounting for the ligands-receptors chemical interaction, the diffusion of receptors along the membrane, and the mechanical deformation of the cell.…”

Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

“…Based on these measurements, we estimated 283ξ to vary between 0.1 − 0.0001 and adopt these values in our simulations. The receptor diffusivity was taken as D = 0.01 µm 2 •s −1 an average value for most cells [14,31,33].…”

Modeling and Simulation of VEGF Receptors Recruitment in Angiogenesis

“…The partial differential equations of the model have been implemented in a computer code, with the ultimate goal to predict conditions for angiogenesis. The FEM code, implemented in the deal.ii open source finite element library, has been validated against codesigned experiments partially discussed in the companion paper [7].…”

“…Codesigned experiments and simulations for VEGFR2 have been recently developed, with biological findings and the predictive ability of the model extensively discussed in [7]. Here, we profoundly describe the modeling of VEGFR2 recruitment in angiogenesis, detailing the thermodynamic description, the weak formulation, and the algorithms for the numerical solution.…”