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New insights in blood vessel formation

April 01, 2016

How vascular tubes build, maintain and adapt continuously perfused lumens to meet local metabolic needs remains poorly understood. Recent studies showed that blood flow itself plays a critical role in the remodelling of vascular networks and suggested it is also required for the lumenization of new vascular connections. However, it is still unknown how haemodynamic forces contribute to the formation of new vascular lumens during blood vessel morphogenesis. An international team of researchers under the direction of Holger Gerhardt (VIB/KU Leuven/Cancer Research UK/MDC/BIH Berlin) found that blood flow drives lumen expansion during sprouting angiogenesis in vivo by inducing spherical deformations of the apical membrane of endothelial cells, in a process that they have termed inverse blebbing.

Holger Gerhardt (VIB/KU Leuven/Cancer Research UK/ MDC/BIH Berlin): "This work combined with previous studies highlights the importance of balanced endothelial cell contractility in allowing the expansion and maintenance of endothelial lumens during blood vessel development."

These results challenge the previous idea that sprouting cells expand lumens independently of blood flow during angiogenesis in vivo through the generation and fusion of intracellular vacuoles. The researchers showed that haemodynamic forces dynamically shape the apical membrane of single or groups of endothelial cells during angiogenesis in vivo to form and expand new lumenized vascular tubes. "We find that this process relies on a tight balance between the forces applied on the membrane and the local contractile responses from the endothelial cells, as impairing this balance either way leads to lumen defects", Holger Gerhardt says.

This finding of inverse blebbing suggests that the process of blebbing, best studied in cell migration and cytokinesis, does not require a specific polarity, but is likely to be generally applicable to situations in which external versus internal pressure differences challenge the stability and elasticity of the actin cortex. It more generally raises the question of the role of apical membrane contractility in the adaptation to varying haemodynamic environments, both during blood vessel morphogenesis, as connections form or remodel, and in pathological settings.

Holger Gerhardt: "Understanding whether and how this plasticity of the apical membrane and its underlying cortex is challenged in pathological conditions, where vessels exhibit altered perfusion and lack organized structure, has the potential to provide deeper insight into mechanisms of vascular adaptation and maladaptation. We will definitely further investigate this."

Alongside the publication of the Holger Gerhardt lab a highlight article from Erez Raz (University of Münster, Institute of Cell Biology) was published. In this article he concludes: 'Overall, this work underscores the significance of dynamic in vivo analysis for the understanding of fundamental processes in cell and developmental biology. Employing improved imaging techniques and the newly-developed powerful genetic tools in the zebrafish model are likely to provide an even deeper understanding of the mechanisms controlling vascular system development, as well as those important for the formation and shaping of other organs, tissues and structures.'

Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo, Gebala et al., Nature Cell Biology 2016

VIB (the Flanders Institute for Biotechnology)

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