Dataset Information

Intercellular Tension Negatively Regulates Angiogenic Sprouting of Endothelial Tip Cells via Notch1-Dll4 Signaling.

ABSTRACT: Mechanical force plays pivotal roles in vascular development during tissue growth and regeneration. Nevertheless, the process by which mechanical force controls the vascular architecture remains poorly understood. Using a systems bioengineering approach, we show that intercellular tension negatively regulates tip cell formation via Notch1-Dll4 signaling in mouse retinal angiogenesis in vivo, sprouting embryoid bodies, and human endothelial cell networks in vitro. Reducing the intercellular tension pharmacologically by a Rho-associated protein kinase inhibitor or physically by single cell photothermal ablation of the capillary networks promotes the expression of Dll4, enhances angiogenic sprouting of tip cells and increases the vascular density. Computational biomechanics, RNA interference, and single cell gene expression analysis reveal that a reduction of intercellular tension attenuates the inhibitory effect of Notch signaling on tip cell formation and induces angiogenic sprouting. Taken together, our results reveal a mechanoregulation scheme for the control of vascular architecture by modulating angiogenic tip cell formation via Notch1-Dll4 signaling.

SUBMITTER: Wang S

PROVIDER: S-EPMC6338428 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Intercellular Tension Negatively Regulates Angiogenic Sprouting of Endothelial Tip Cells via Notch1-Dll4 Signaling.

Wang Shue S Sun Jian J Xiao Yuan Y Lu Yi Y Zhang Donna D DD Wong Pak Kin PK

Advanced biosystems 20170131 1-2

Mechanical force plays pivotal roles in vascular development during tissue growth and regeneration. Nevertheless, the process by which mechanical force controls the vascular architecture remains poorly understood. Using a systems bioengineering approach, we show that intercellular tension negatively regulates tip cell formation via Notch1-Dll4 signaling in mouse retinal angiogenesis in vivo, sprouting embryoid bodies, and human endothelial cell networks <i>in vitro</i>. Reducing the intercellula ...[more]

PMID: 30662935

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Project description:Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.

Dataset Information

Intercellular Tension Negatively Regulates Angiogenic Sprouting of Endothelial Tip Cells via Notch1-Dll4 Signaling.

Publications

Intercellular Tension Negatively Regulates Angiogenic Sprouting of Endothelial Tip Cells via Notch1-Dll4 Signaling.

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