Vascular morphogenesis

Introduction

vascular-plexus

Vascular plexus in quail embryo

Vasculogenesis, the de novo formation of blood vessels, is a crucial process in the embryo as well as for successful tissue engineering. One of the earliest steps in this process is the coalescence of isolated endothelial cell into polygonal networks, but remains poorly understood.

Although it is clear that factors such as vascular endothelial growth factor (VEGF) are required, the mechanisms by which they drive cells into connected networks remain unclear.


Paracrine signaling in vasculogenesis

Together with dr. Alvaro Kohn-Luque and others, I have developed computational cell-based models to study the formation of vascular networks, based on the multi-scale coupling of reaction-diffusion systems representing VEGF dynamics to a cellular Potts model describing cell shape and chemotactic motility.

Simulated vascular network through paracrine signaling

In contrast to existing models, we assumed that VEGF acts as a paracrine (rather than an autocrine) factor that is produced by nearby endodermal cells and invoking a chemotactic response in endothelial cells. We further assumed that VEGF binds to extracellular matrix molecules and thereby form guidance cues for endothelial cells.

Through simulation of our computational model, we could show that this mechanism can result in the formation of cellular networks. Moreover, the cellular network are highly similar to in vivo vascular networks from quail embryos, as shown by quantitative morphometric comparison.

VEGF matrix retention in vitro

More recently, we collaborated with prof. Takashi Miura to investigate in vitro formation of vascular networks and test predictions generated by the retention model. There, we observed that externally added (fluorescent) VEGF is found close to cells, as we would expect under the idea of matrix retention.

phys-biol-2013

Fluorescent VEGF localizes near cells. Left: brightfield. Right: VEGF-F (bar: 50 um).

Using techniques such as FRAP and ELISA, we could measure the diffusivity and decay of VEGF as well as its rates of binding/unbinding to/from the extracellular matrix. Plugging these realistic biophysical measurements back in our computational model, we could confirm the establishment of vascular networks under the assumption of VEGF matrix retention. These findings thus suggest that the extracellular matrix, apart from providing mechanical support, also acts to provide chemical guidance by retention of chemotactants during vascular morphogenesis.