Formation of VEGF isoform-specific spatial distributions governing angiogenesis: computational analysis

Prakash Vempati,Feilim Mac Gabhann,Aleksander S Popel

doi:10.1186/1752-0509-5-59

Prakash Vempati, Feilim Mac Gabhann + Show 1 more

Open Access

https://doi.org/10.1186/1752-0509-5-59

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Abstract

BackgroundThe spatial distribution of vascular endothelial growth factor A (VEGF) is an important mediator of vascular patterning. Previous experimental studies in the mouse hindbrain and retina have suggested that VEGF alternative splicing, which controls the ability of VEGF to bind to heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays a key role in controlling VEGF diffusion and gradients in tissues. Conversely, proteolysis notably by matrix metalloproteinases (MMPs), plays a critical role in pathological situations by releasing matrix-sequestered VEGF and modulating angiogenesis. However, computational models have predicted that HSPG binding alone does not affect VEGF localization or gradients at steady state.ResultsUsing a 3D molecular-detailed reaction-diffusion model of VEGF ligand-receptor kinetics and transport, we test alternate models of VEGF transport in the extracellular environment surrounding an endothelial sprout. We show that differences in localization between VEGF isoforms, as observed experimentally in the mouse hindbrain, as well as the ability of proteases to redistribute VEGF in pathological situations, are consistent with a model where VEGF is endogenously cleared or degraded in an isoform-specific manner. We use our predictions of the VEGF distribution to quantify a tip cell's receptor binding and gradient sensing capacity. A novel prediction is that neuropilin-1, despite functioning as a coreceptor to VEGF165-VEGFR2 binding, reduces the ability of a cell to gauge the relative steepness of the VEGF distribution. Comparing our model to available in vivo vascular patterning data suggests that vascular phenotypes are most consistently predicted at short range by the soluble fraction of the VEGF distributions, or at longer range by matrix-bound VEGF detected in a filopodia-dependent manner.ConclusionsIsoform-specific VEGF degradation provides a possible explanation for numerous examples of isoform specificity in VEGF patterning and examples of proteases relocation of VEGF upon release.

Highlights

The spatial distribution of vascular endothelial growth factor A (VEGF) is an important mediator of vascular patterning
The computational model predicts that the steady-state distribution of soluble VEGF is isoform-independent when considering only diffusion and matrix binding When VEGF is secreted, extracellular heparan sulfate proteoglycans (HSPGs) are predicted not to influence the distribution of the soluble fraction of VEGF (Figure 3A vs. 3B); nor do they influence receptor signaling (Figure 3, bar graphs), assuming VEGF-HSPG complexes in the extracellular matrix (ECM) cannot directly ligate VEGF receptors
In the present study, we have identified a general mechanism of VEGF transport that explains experimental data regarding VEGF isoform patterning and proteolytic release at steady state, that of isoform specific degradation

Summary

Introduction

The spatial distribution of vascular endothelial growth factor A (VEGF) is an important mediator of vascular patterning. VEGF is primarily secreted as VEGF120, VEGF164, and VEGF188 (human VEGF is one amino acid longer: VEGF121, VEGF165, VEGF189) [3]; longer isoforms include C-terminal motifs that increase binding to heparin and HSPGs in the ECM [21,22]. This increased matrix affinity can reduce the effective diffusivity of the isoform, altering the spatial gradient. Systems secreting VEGF188 show the greatest levels of ECM and basement membrane VEGF deposition [6,24]

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