Variations in Tip Cell Proximity and sFlt1 Gradients Alter VEGF Receptor Activation in a Computational Model

Abstract

Soluble VEGF receptor 1 (sFlt1) modulates the guidance cues provided to sprouting blood vessels by vascular endothelial growth factor (VEGF). Based on experimental observations in developing vasculature, we hypothesize that a local reduction in sFlt1 expression can control angiogenesis by increasing local VEGF receptor 2 (Flk1) signaling. To quantify sFlt1 modulation of VEGF signaling, we developed an experimentally-based computational model describing spatial transport of VEGF and its receptors. Our model represents the local environment of a single blood vessel and nearby tissue: parenchymal cells secrete VEGF, which diffuses and binds extracellular matrix and sFlt1; VEGF binds endothelial cells via membrane-bound Flt1 and Flk1; and endothelial cells secrete sFlt1. The model allows us to quantify the relative contributions of VEGF sequestration by sFlt1 in the interstitial space and sFlt1 heterodimerization with surface receptors, both of which can decrease VEGF receptor signaling. Our simulations predict that when a sprout-leading tip cell secretes less sFlt1 than neighboring cells, local sFlt1 sequestration of VEGF is decreased, thus increasing VEGF-Flk1 levels on the surface of the low-sFlt1 secreting tip cell. We also show that the proximity of neighboring tip cells may alter VEGF receptor binding. Supported by NIH R00HL093219 (FMG), R01HL43174 (VLB), F32HL95359, T32CA9156 & AHA 0826082E (JCC)