Abstract
Experimental data indicates that soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1) modulates the guidance cues provided to sprouting blood vessels by VEGF-A. To better delineate the role of sFlt-1 in VEGF signaling, we have developed an experimentally based computational model. This model describes dynamic spatial transport of VEGF, and its binding to receptors Flt-1 and Flk-1, in a mouse embryonic stem cell model of vessel morphogenesis. The model represents the local environment of a single blood vessel. Our simulations predict that blood vessel secretion of sFlt-1 and increased local sFlt-1 sequestration of VEGF results in decreased VEGF–Flk-1 levels on the sprout surface. In addition, the model predicts that sFlt-1 secretion increases the relative gradient of VEGF–Flk-1 along the sprout surface, which could alter endothelial cell perception of directionality cues. We also show that the proximity of neighboring sprouts may alter VEGF gradients, VEGF receptor binding, and the directionality of sprout growth. As sprout distances decrease, the probability that the sprouts will move in divergent directions increases. This model is a useful tool for determining how local sFlt-1 and VEGF gradients contribute to the spatial distribution of VEGF receptor binding, and can be used in conjunction with experimental data to explore how multi-cellular interactions and relationships between local growth factor gradients drive angiogenesis.
Highlights
Angiogenesis is the growth of new blood vessels from an existing vascular network
SFlt-1 SECRETION LOWERS AVAILABLE vascular endothelial growth factor (VEGF) CONCENTRATION Figure 2 shows the predicted gradients of soluble VEGF, sFlt-1, VEGF–sFlt-1, and extracellular matrix (ECM)-bound VEGF complexes along straight lines across the interstitial space after 10 h of sFlt-1 secretion
To quantify the extent to which sFlt-1 alters VEGF signaling in a biological context, we have developed an experimentally based computational model describing dynamic spatial transport of VEGF and its receptors, based on blood vessel morphogenesis during mouse embryonic stem (ES)-cell differentiation
Summary
Angiogenesis is the growth of new blood vessels from an existing vascular network While it has been studied extensively in pathological conditions such as cancer, angiogenesis is essential for organ development and recovery of tissues from injury. This complex, multistep process is regulated, in part, by the extracellular ligands of the vascular endothelial growth factor (VEGF) family. VEGF ligands bind to and activate receptor tyrosine kinases on the endothelial cell surface, initiating downstream signaling that drives cellular behaviors such as proliferation and migration, culminating in angiogenesis (Keck et al, 1989; Leung et al, 1989; Olsson et al, 2006; Shibuya and Claesson-Welsh, 2006). Flt-1 and Flk-1 are both essential for vascular development and viability, since genetic deletion of either gene in mice causes death in utero (Fong et al, 1995; Shalaby et al, 1995)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
