Simulations Predict that Competing Gradients of VEGF and sFlt1 Alter VEGF Receptor Activation

Abstract

We have created an experimentally-based computational model describing spatial transport of vascular endothelial growth factor (VEGF) and its receptors to quantitatively understand how guidance cues may modulate blood vessel sprout growth. VEGF binds to endothelial cells and initiates angiogenesis. Both VEGF concentration and VEGF gradients may control sprout formation. Soluble VEGF receptor 1 (sFlt1) can bind and sequester VEGF. Based on observations in developing vasculature, we hypothesize that a local reduction in sFlt1 expression can increase locally available VEGF and thus control angiogenesis. However, the complex VEGF interaction network makes it difficult to isolate how individual proteins contribute to the spatial distribution of the growth factor using experiments alone. Our computational model represents the local environment of a single blood vessel and nearby tissue and directly incorporates the network of VEGF interactions. In the model, parenchymal cells secrete VEGF, which diffuses through interstitial space and binds extracellular matrix (ECM) and sFlt1. VEGF binds endothelial cells via membrane-bound receptors Flt1 and Flk1, and endothelial cells secrete sFlt1. Additionally, the model accounts for degradation of VEGF and sFlt1 as well as internalization of receptor-bound ligands. Using partial differential equations, we simulate this system, which is constrained by experimentally-derived parameters. Our simulations show that when a sprout-leading tip cell secretes less sFlt1 than neighboring cells, there is decreased local sFlt1 sequestration of VEGF, thus resulting in augmented VEGF-Flk1 levels on the surface of the low-sFlt1 secreting tip cell. This could lead to sprout generation. We also show how variations in sFlt1 secretion and tip cell configuration may affect the gradients of guidance cues and directionality of sprout growth.