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A coupled model of neovessel growth and matrix mechanics describes and predicts angiogenesis in vitro.

ABSTRACT: During angiogenesis, sprouting microvessels interact with the extracellular matrix (ECM) by degrading and reorganizing the matrix, applying traction forces, and producing deformation. Morphometric features of the resulting microvascular network are affected by the interaction between the matrix and angiogenic microvessels. The objective of this study was to develop a continuous-discrete modeling approach to simulate mechanical interactions between growing neovessels and the deformation of the matrix in vitro. This was accomplished by coupling an existing angiogenesis growth model which uses properties of the ECM to regulate angiogenic growth with the nonlinear finite element software FEBio (www.febio.org). FEBio solves for the deformation and remodeling of the matrix caused by active stress generated by neovessel sprouts, and this deformation was used to update the ECM into the current configuration. After mesh resolution and parameter sensitivity studies, the model was used to accurately predict vascular alignment for various matrix boundary conditions. Alignment primarily arises passively as microvessels convect with the deformation of the matrix, but active alignment along collagen fibrils plays a role as well. Predictions of alignment were most sensitive to the range over which active stresses were applied and the viscoelastic time constant in the material model. The computational framework provides a flexible platform for interpreting in vitro investigations of vessel-matrix interactions, predicting new experiments, and simulating conditions that are outside current experimental capabilities.

SUBMITTER: Edgar LT

PROVIDER: S-EPMC4447608 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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A coupled model of neovessel growth and matrix mechanics describes and predicts angiogenesis in vitro.

Edgar Lowell T LT Maas Steve A SA Guilkey James E JE Weiss Jeffrey A JA

Biomechanics and modeling in mechanobiology 20141128 4

During angiogenesis, sprouting microvessels interact with the extracellular matrix (ECM) by degrading and reorganizing the matrix, applying traction forces, and producing deformation. Morphometric features of the resulting microvascular network are affected by the interaction between the matrix and angiogenic microvessels. The objective of this study was to develop a continuous-discrete modeling approach to simulate mechanical interactions between growing neovessels and the deformation of the ma ...[more]

PMID: 25429840

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Project description:During angiogenesis, growing neovessels must effectively navigate through the tissue space as they elongate and subsequently integrate into a microvascular network. While time series microscopy has provided insight into the cell activities within single growing neovessel sprouts, less is known concerning neovascular dynamics within a large angiogenic tissue bed. Here, we developed a time-lapse imaging technique that allowed visualization and quantification of sprouting neovessels as they form and grow away from adult parent microvessels in three dimensions over cubic millimeters of matrix volume during the course of up to 5 days on the microscope. Using a new image acquisition procedure and novel morphometric analysis tools, we quantified the elongation dynamics of growing neovessels and found an episodic growth pattern accompanied by fluctuations in neovessel diameter. Average elongation rate was 5 ?m/h for individual vessels, but we also observed considerable dynamic variability in growth character including retraction and complete regression of entire neovessels. We observed neovessel-to-neovessel directed growth over tens to hundreds of microns preceding tip-to-tip inosculation. As we have previously described via static 3D imaging at discrete time points, we identified different collagen fibril structures associated with the growing neovessel tip and stalk, and observed the coordinated alignment of growing neovessels in a deforming matrix. Overall analysis of the entire image volumes demonstrated that although individual neovessels exhibited episodic growth and regression, there was a monotonic increase in parameters associated with the entire vascular bed such as total network length and number of branch points. This new time-lapse imaging approach corroborated morphometric changes in individual neovessels described by us and others, as well as captured dynamic neovessel behaviors unique to days-long angiogenesis within the forming neovascular network.

Project description:Mechanical interactions during angiogenesis, i.e., traction applied by neovessels to the extracellular matrix and the corresponding deformation, are important regulators of growth and neovascularization. We have previously designed, implemented, and validated a coupled model of angiogenesis in which a discrete microvessel growth model interacts with a continuous finite element mesh through the application of local remodeling sprout stresses (Edgar et al. in Biomech Model Mechanobiol, 2014). However, the initial implementation of this framework does not take matrix density into account when determined these remodeling stresses and is therefore insufficient for the study of angiogenesis within heterogeneous matrix environments such as those found in vivo. The objective of this study was to implement sensitivity to matrix density in the active stress generation within AngioFE in order to allow the study of angiogenic growth within a heterogeneous density environment. We accomplished this by scaling active sprout stresses relative to local matrix density using a scaling factor previously determined from experimental data. We then exercised the new functionality of the model by simulating angiogenesis within four different scenarios: homogeneous density, a narrow gap model, and matrix density gradient, and a construct subjected to repeated loading/unloading and preconditioning. These numerical experiments predicted heterogeneous matrix density in the initially homogeneous case, the closure and alignment of microvessels along a low-density gap, the formation of a unique cap-like structure during angiogenesis within a density gradient, and the alignment of microvessels in the absence of applied load due to preconditioning. The result of these in silico investigations demonstrate how matrix heterogeneity affects neovascularization and matrix deformation and provides a platform for studying angiogenesis in complicated and multi-faceted mechanical environments that microvessels experience in vivo.

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Project description:Angiogenesis is fundamentally required for the initialization, development and metastatic spread of cancer. A rapidly expanding number of new experimental, chemical modulators of endothelial cell function have been described for the therapeutic inhibition of angiogenesis in cancer. Despite this expansion, there has been very limited parallel growth of in vitro angiogenesis models or experimental tools. Here we present the Responsive Angiogenic Implanted Network (RAIN)-Droplet model and novel angiogenesis assay using an endothelial cell culture model of microvascular endothelial cells encapsulated in a spontaneously self-assembling, toroidal hydrogel droplet uniquely yielding discrete, pre-formed, angiogenic networks that may be embedded in 3D matrices. On embedding, radial growth of capillary-like sprouts and cell invasion was observed. The sprouts formed not only as outgrowths from endothelial cells on the surface of the droplets, but also, uniquely, from the pre-formed network structures within the droplet. We demonstrate proof of principle for the utility of the model showing significant inhibition of sprout formation (P<0.001) in the presence of bevacizumab, an anti-angiogenic antibody. Using the RAIN-Droplet assay, we also demonstrate a novel dose-dependent pro-angiogenic function for the characteristically anti-angiogenic multi-kinase inhibitor sorafenib. Exposure of endothelial cells in 3D culture to low, non-lethal doses (<1 ?M) of sorafenib after initiation of sprouting resulted in the formation of significantly (P<0.05) more endothelial sprouts compared with controls over a 48-h period. Higher doses of sorafenib (5 ?M) resulted in a significant (P<0.05) reduction of sprouting over the same time period. The RAIN-Droplet model is a highly versatile and simply constructed 3D focal sprouting approach well suited for the study of vascular morphogenesis and for preclinical testing of drugs. Furthermore, the RAIN-Droplet model has facilitated the discovery of a novel pro-angiogenic capacity for sorafenib, which may impact the clinical application and dosing regimen of that drug.

Dataset Information

A coupled model of neovessel growth and matrix mechanics describes and predicts angiogenesis in vitro.

Publications

A coupled model of neovessel growth and matrix mechanics describes and predicts angiogenesis in vitro.

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