Mechanical Interaction of Angiogenic Microvessels With the Extracellular Matrix

Abstract

Angiogenesis is the process by which new blood vessels sprout from existing blood vessels, enabling new vascular elements to be added to an existing vasculature. This review discusses our investigations into the role of cell-matrix mechanics in the mechanical regulation of angiogenesis. The experimental aspects of the research are based on in vitro experiments using an organ culture model of sprouting angiogenesis with the goal of developing new treatments and techniques to either promote or inhibit angiogenic outgrowth, depending on the application. Computational simulations were performed to simulate angiogenic growth coupled to matrix deformation, and live two-photon microscopy was used to obtain insight into the dynamic mechanical interaction between angiogenic neovessels and the extracellular matrix. In these studies, we characterized how angiogenic neovessels remodel the extracellular matrix (ECM) and how properties of the matrix such as density and boundary conditions influence vascular growth and alignment. Angiogenic neovessels extensively deform and remodel the matrix through a combination of applied traction, proteolytic activity, and generation of new cell-matrix adhesions. The angiogenic phenotype within endothelial cells is promoted by ECM deformation and remodeling. Sensitivity analysis using our finite element model of angiogenesis suggests that cell-generated traction during growth is the most important parameter controlling the deformation of the matrix and, therefore, angiogenic growth and remodeling. Live two-photon imaging has also revealed numerous neovessel behaviors during angiogenesis that are poorly understood such as episodic growth/regression, neovessel colocation, and anastomosis. Our research demonstrates that the topology of a resulting vascular network can be manipulated directly by modifying the mechanical interaction between angiogenic neovessels and the matrix.

Matrix density alters zyxin phosphorylation, which limits peripheral process formation and extension in endothelial cells invading 3D collagen matrices

“…Tractional forces modulate angiogenesis (Ingber and Folkman, 1989), control EC branching (Fischer et al, 2009), affect formation of capillary-like structures (Deroanne et al, 2001;Sieminski et al, 2004;Kniazeva and Putnam, 2009;Edgar et al, 2014b), and regulate branching of mammary epithelial cells (Gjorevski and Nelson, 2010). Altering matrix density changed the formation of extended (tip) processes in fibroblasts (Grinnell and Petroll, 2010), tumor cells (Provenzano et al, 2009), and ECs (shown here), which we have shown previously extend and retract from the tips of ECs as they navigate through 3D collagen matrices ).…”

A Comparative Study of Collagen Matrix Density Effect on Endothelial Sprout Formation Using Experimental and Computational Approaches

“…Furthermore, Mathematical investigations of angiogenesis have employed continuous, discrete, and mechanical models to describe a variety of dynamics believed to influence angiogenesis. 2,9,13,16,17,36,42,50,58 However, despite clear evidence that the ECM is crucial to cellular behavior and vascular patterning, most models of angiogenesis neglect the dynamic interaction between endothelial cells and the ECM. Until recently, no single mathematical model existed that (a) couples multiple time and length scales, (b) generates realistic capillary structures, including branching and anastomoses, without a priori prescribing rules and probabilities to these events, and (c) considers the complex biochemical and mechanical interactions that occur between endothelial cells and the ECM.…”

Biofabrication of Vascular Networks

“…Physically constraining a collagen I-based stroma, either during angiogenesis or the postangiogenesis remodeling phase, profoundly influences vascular topology [28,104]. The extent by which stromal mechanics influences the vasculature appears to reflect the degree and orientation of stromal matrix deformation [105,106]. Forces applied to collagen-based matrices are rapidly dissipated and do not persist due to the highly viscoelastic properties of collagen and other native gels [107].…”