# A mechanistic computational model of HGF-VEGF-mediated endothelial cell proliferation and vascular permeability

## TL;DR

This paper presents a computational model showing how HGF and VEGF affect blood vessel growth and permeability, revealing how they interact in disease-related processes.

## Contribution

A novel data-driven model of HGF and VEGF signaling in endothelial cells that explains their distinct effects on vascular permeability.

## Key findings

- HGF can counteract VEGF-induced endothelial cell permeability in a dose-dependent manner.
- RAC1-PAK1 activation via phosphorylation explains differences in permeability between HGF and VEGF.
- HGF does not require VEGFR2 activation to influence endothelial cell behavior.

## Abstract

Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are important pro-angiogenic factors in angiogenesis-dependent diseases. While sharing some signaling pathways, their contrasting effect on vascular permeability remains under investigation. To explore how these factors promote angiogenesis, we developed, calibrated, and validated a data-driven mechanistic computational model of HGF and VEGF signaling in endothelial cells (ECs). We proposed that variations in permeability profiles may stem from RAC1-PAK1 activation via site-specific phosphorylation. By introducing permeability and proliferation indices, our simulations indicated a dose-dependent effect of VEGF that hampered the ability of HGF to promote vascular stability. Our simulations indicate that HGF did not require VEGFR2 activation to affect permeability and proliferation. This model has the potential to be applicable and helpful in analyzing angiogenesis-dependent diseases. It provided insights into the mechanisms of EC proliferation and vascular permeability induced by HGF and VEGF and permitted evaluation of their separate or combined effects.

•Integrative mechanistic computational model of HGF/VEGF signaling in endothelial cells•Dose-based modeling revealed that HGF can counteract VEGF-induced EC permeability•Sensitivity analysis revealed context-specific regulators of EC permeability•PAK1 phosphorylation sites drove VEGF/HGF-specific differences in EC permeability

Integrative mechanistic computational model of HGF/VEGF signaling in endothelial cells

Dose-based modeling revealed that HGF can counteract VEGF-induced EC permeability

Sensitivity analysis revealed context-specific regulators of EC permeability

PAK1 phosphorylation sites drove VEGF/HGF-specific differences in EC permeability

Integrative aspects of cell biology; Experimental models in systems biology; In silico biology; Biological constraints