Abstract
Angiogenesis is regulated by the local microenvironment, including the mechanical interactions between neovessel sprouts and the extracellular matrix (ECM). However, the mechanisms controlling the relationship of mechanical and biophysical properties of the ECM to neovessel growth during sprouting angiogenesis are just beginning to be understood. In this research, we characterized the relationship between matrix density and microvascular topology in an in vitro 3D organ culture model of sprouting angiogenesis. We used these results to design and calibrate a computational growth model to demonstrate how changes in individual neovessel behavior produce the changes in vascular topology that were observed experimentally. Vascularized gels with higher collagen densities produced neovasculatures with shorter vessel lengths, less branch points, and reduced network interconnectivity. The computational model was able to predict these experimental results by scaling the rates of neovessel growth and branching according to local matrix density. As a final demonstration of utility of the modeling framework, we used our growth model to predict several scenarios of practical interest that could not be investigated experimentally using the organ culture model. Increasing the density of the ECM significantly reduced angiogenesis and network formation within a 3D organ culture model of angiogenesis. Increasing the density of the matrix increases the stiffness of the ECM, changing how neovessels are able to deform and remodel their surroundings. The computational framework outlined in this study was capable of predicting this observed experimental behavior by adjusting neovessel growth rate and branching probability according to local ECM density, demonstrating that altering the stiffness of the ECM via increasing matrix density affects neovessel behavior, thereby regulated vascular topology during angiogenesis.
Highlights
Angiogenesis is the generation of new vascular elements from existing vasculature
We explored the relationship between angiogenesis and the mechanical properties of the extracellular matrix (ECM) using a three-dimensional (3D) organ culture model of microvessel fragments within a type-I collagen gel [11,12,13,14]
We found that increases in matrix density significantly limited angiogenesis (Fig. 3)
Summary
Angiogenesis is the generation of new vascular elements from existing vasculature. During angiogenesis, sprouting endothelial cells degrade the basement membrane with matrix metalloproteinases (MMPs) [1,2] and apply traction to and migrate along components of the extracellular matrix (ECM) [3], resulting in neovessel elongation. We explored the relationship between angiogenesis and the mechanical properties of the ECM using a three-dimensional (3D) organ culture model of microvessel fragments within a type-I collagen gel [11,12,13,14]. In this model of sprouting angiogenesis, neovessels sprouting from whole microvessels cultured in a 3D gel, that was free to contract in all directions, grow into a randomly oriented network [12,13,14]. When contraction was prevented along the long-axis of rectangular gels, neovessels and collagen fibrils were aligned parallel to the constrained axis [13,14]
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