Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Measuring and modeling dynamics of VEGF retention in vascular patterning
Walter de Back

Last modified: 2014-06-09


How blood vessel networks form is a key question in developmental biology as well as in tissue engineering. Although it is known that chemoattractants such as vascular endothelial growth factor (VEGF) are important in this process, their role in driving endothelial cells to assemble into network patterns remains under debate. The combination of the cellular Potts model (CPM) with reaction-diffusion systems forms an appropriate framework to represent the feedback between VEGF dynamics and endothelial cell motility. We have used this framework in previous work to theoretically demonstrate that cellular networks can arise as a result of chemotaxis towards paracrine VEGF bound to extracellular matrix components [Köhn-Luque et al., 2011]. Now, to test this hypothesis experimentally, we have quantitatively analysed the dynamics of VEGF in a controlled in vitro situation of human umbilical vascular endothelial cells (HUVECs) in Matrigel [Köhn-Luque et al., 2013]. 
Using a variety of techniques such as fluorescence recovery after photobleaching (FRAP), we demonstrate that VEGF accumulates in pericellular areas and decays in a cell-dependent manner and that binding/unbinding dominates diffusion near cells, providing experimental evidence for matrix-retention of VEGF around endothelial cells. To investigate network formation under realistic biophysical conditions, we parameterized and calibrated the CPM/reaction-diffusion model using our measured kinetic rates for VEGF dynamics. Indeed, simulation of this quantitative multiscale model using the Morpheus modeling environment [Starruß et al., 2014] confirms the formation of cellular networks under these conditions on a realistic time scale.
Together, these theoretical and experimental results demonstrate that matrix binding of exogenous VEGF is a key regulator of vascular pattern formation. Additionally, the cycle of theoretical modeling, experimental validation and subsequent quantitative modeling demonstrates the role and value of multiscale cellular Potts models for the study of complex biological processes in multicellular systems biology.


- A. Köhn-Luque, W. de Back, J. Starruß, A. Mattioti, A. Deutsch, J-M. Pérez-Pomares, M. A. Herrero (2011) Early Embryonic Vascular Patterning by Matrix-Mediated Paracrine Signalling: A Mathematical Model Study. PLoS ONE 6(9):e24175,.
- A. Köhn-Luque, W. de Back, Y. Yamaguchi, K. Yoshimura, M. A. Herrero, T. Miura (2013) Dynamics of VEGF Matrix-Retention in Vascular Network Patterning. Physical Biology, 10:066007.
- J. Starruß, W. de Back, L. Brusch, A. Deutsch (2014) Morpheus: a user-friendly modeling environment for multiscale and multicellular systems biology. Bioinformatics, btt772.