Network Analysis of Extracellular Matrix Microenvironment Signaling in Vasculogenesis
Aberrant blood vessel formation is implicated in many diseases. Physiological and pathological vascularization is governed by a balance of pro- and anti-neovascular signals in the microenvironment that control a neovascular switch. Several anti-neovascular drugs targeting specific molecules are under investigation; however, the dynamics of the neovascular switch are poorly understood, so it is difficult to predict how the vasculature will respond to particular therapeutic regimens. The purpose of the current research is to investigate the dynamics of the extracellular matrix molecules that promote and inhibit neovascularization through the mechanotransduction pathway. We focused on force-dependent signaling through β1 integrin and investigated the dynamics by building a computational model of the effects of pro-neovascular type I collagen, type IV collagen, and type IV collagen-derived anti-neovascular fragments on vessel growth in vivo and in vitro, including matrix metalloproteinase signaling important for the feedback between the endothelial cells and the matrix. Using data from a three-dimensional tissue culture system of endothelial colony forming cells embedded in type I oligomeric collagen, as well as various sources in the experimental literature, we used the computational model to understand the mechanism by which β1 integrin integrates the mechanical signals of interest. Because the available data is largely qualitative, we used optimal scaling and multi-objective optimization to facilitate its use with the computational model. We focused on two specific mechanisms: direct inhibition of matrix metalloproteinase (MMP) activation by type IV collagen fragments and positive autoregulation of recruitment of β1 integrin to the focal adhesion site. We found that in order to fit the experimental data, positive autoregulation is necessary for integrin dynamics and the dominant mechanism of inhibition of MMP activation by type IV collagen fragments is through indirect means. With further extension of this model, we can investigate downstream signaling that guides vasculogenesis and understand the dynamics of therapeutics that utilize this pathway.
Umulis, Purdue University.
Systematic biology|Biomedical engineering|Biomechanics
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