The Role of Mechanical Stresses in Angiogenesis

Shiu, Yan Ting; Weiss, Jeffrey A.; Hoying, James B.; Iwamoto, Matthew N.; Joung, InSuk; Quam, Cole T.

doi:10.1615/critrevbiomedeng.v33.i5.10

Cited by 91 publications

(44 citation statements)

References 344 publications

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“…Therefore, there has been increasing research interest into the regulatory mechanisms behind angiogenesis, with the hope of developing new treatments and techniques to either promote or inhibit angiogenic outgrowth depending on the application. Angiogenesis is highly sensitive to both the chemical and mechanical microenvironment [4][5][6]. Although extensive research has been performed regarding the chemical regulation of angiogenesis, the mechanical factors that regulate angiogenesis remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Mechanical Interaction of Angiogenic Microvessels With the Extracellular Matrix

Edgar

Hoying

Utzinger

et al. 2014

Journal of Biomechanical Engineering

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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.

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Section: Introductionmentioning

confidence: 99%

Mechanical Interaction of Angiogenic Microvessels With the Extracellular Matrix

Edgar

Hoying

Utzinger

et al. 2014

Journal of Biomechanical Engineering

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“…As a result, the role in angiogenesis of haemodynamic factors and mechanochemical forces cannot be studied in this system [210]. Aortic explants contain macrophages and dendritic cells, but lack other immune cell types, which can however be added to the cultures.…”

Section: Introductionmentioning

confidence: 99%

The aortic ring model of angiogenesis: a quarter century of search and discovery

Nicosia

2009

J Cellular Molecular Medi

102

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The aortic ring model has become one of the most widely used methods to study angiogenesis and its mechanisms. Many factors have contributed to its popularity including reproducibility, cost effectiveness, ease of use and good correlation with in vivo studies. In this system aortic rings embedded in biomatrix gels and cultured under chemically defined conditions generate arborizing vascular outgrowths which can be stimulated or inhibited with angiogenic regulators. Originally based on the rat aorta, the aortic ring model was later adapted to the mouse for the evaluation of specific molecular alterations in genetically modified animals. Viral transduction of the aortic rings has enabled investigators to overexpress genes of interest in the aortic cultures. Experiments on angiogenic mechanisms have demonstrated that formation of neovessels in aortic cultures is regulated by macrophages, pericytes and fibroblasts through a complex molecular cascade involving growth factors, inflammatory cytokines, axonal guidance cues, extracellular matrix (ECM) molecules and matrix-degrading proteolytic enzymes. These studies have shown that endothelial sprouting can be effectively blocked by depleting the aortic explants of macrophages or by interfering with the angiogenic cascade at multiple levels including growth factor signalling, cell adhesion and proteolytic degradation of the ECM. In this paper, we review the literature in this field and retrace the journey from our first morphological descriptions of the aortic outgrowths to the latest breakthroughs in the cellular and molecular regulation of aortic vessel growth and regression.

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“…38 While there are many factors that control angiogenesis, little is known as to the how the mechanical microenvironment influences the topology of a growing vasculature. 11,40 …”

Section: Introductionmentioning

confidence: 99%

In Silico Investigation of Angiogenesis with Growth and Stress Generation Coupled to Local Extracellular Matrix Density

2015

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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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The Role of Mechanical Stresses in Angiogenesis

Cited by 91 publications

References 344 publications

Mechanical Interaction of Angiogenic Microvessels With the Extracellular Matrix

Mechanical Interaction of Angiogenic Microvessels With the Extracellular Matrix

The aortic ring model of angiogenesis: a quarter century of search and discovery

In Silico Investigation of Angiogenesis with Growth and Stress Generation Coupled to Local Extracellular Matrix Density

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