Dataset Information

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.

Project description:Extracellular matrix (ECM)-derived bioscaffolds have been shown to elicit tissue repair through retention of bioactive signals. Given that the adventitia of large blood vessels is a richly vascularized microenvironment, we hypothesized that perivascular ECM contains bioactive signals that influence cells of blood vessel lineages. ECM bioscaffolds were derived from decellularized human and porcine aortic adventitia (hAdv and pAdv, respectively) and then shown have minimal DNA content and retain elastin and collagen proteins. Hydrogel formulations of hAdv and pAdv ECM bioscaffolds exhibited gelation kinetics similar to ECM hydrogels derived from porcine small intestinal submucosa (pSIS). hAdv and pAdv ECM hydrogels displayed thinner, less undulated, and fibrous microarchitecture reminiscent of native adventitia, with slight differences in ultrastructure visible in comparison to pSIS ECM hydrogels. Pepsin-digested pAdv and pSIS ECM bioscaffolds increased proliferation of human adventitia-derived endothelial cells and this effect was mediated in part by basic fibroblast growth factor (FGF2). Human endothelial cells cultured on Matrigel substrates formed more numerous and longer tube-like structures when supplemented with pAdv ECM bioscaffolds, and FGF2 mediated this matrix signaling. ECM bioscaffolds derived from pAdv promoted FGF2-dependent in vivo angiogenesis in the chick chorioallantoic membrane model. Using an angiogenesis-focused protein array, we detected 55 angiogenesis-related proteins, including FGF2 in hAdv, pAdv and pSIS ECMs. Interestingly, 19 of these factors were less abundant in ECMs bioscaffolds derived from aneurysmal specimens of human aorta when compared with non-aneurysmal (normal) specimens. This study reveals that Adv ECM hydrogels recapitulate matrix fiber microarchitecture of native adventitia, and retain angiogenesis-related actors and bioactive properties such as FGF2 signaling capable of influencing processes important for angiogenesis. This work supports the use of Adv ECM bioscaffolds for both discovery biology and potential translation towards microvascular regeneration in clinical applications.

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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