WASp controls oriented migration of endothelial cells to achieve functional vascular patterning.

André Rosa,Baptiste Coxam,Alexandra Klaus-Bergmann,Wolfgang Giese,Russell T Collins,Katja Meier,Eireen Bartels-Klein,Lowell T Edgar,Anna Szymborska,Miguel O Bernabeu,Silvanus Alt,Holger Gerhardt

doi:10.1242/dev.200195

Abstract

ABSTRACTEndothelial cell migration and proliferation are essential for the establishment of a hierarchical organization of blood vessels and optimal distribution of blood. However, how these cellular processes are quantitatively coordinated to drive vascular network morphogenesis remains unknown. Here, using the zebrafish vasculature as a model system, we demonstrate that the balanced distribution of endothelial cells, as well as the resulting regularity of vessel calibre, is a result of cell migration from veins towards arteries and cell proliferation in veins. We identify the Wiskott-Aldrich Syndrome protein (WASp) as an important molecular regulator of this process and show that loss of coordinated migration from veins to arteries upon wasb depletion results in aberrant vessel morphology and the formation of persistent arteriovenous shunts. We demonstrate that WASp achieves its function through the coordination of junctional actin assembly and PECAM1 recruitment and provide evidence that this is conserved in humans. Overall, we demonstrate that functional vascular patterning in the zebrafish trunk is established through differential cell migration regulated by junctional actin, and that interruption of differential migration may represent a pathomechanism in vascular malformations.

Highlights

The formation of a functional network of blood vessels with precisely controlled hierarchy and morphology is a crucial process during embryogenesis, development and disease progression
The zebrafish trunk vasculature develops as the result of collective migration, where sprouts originating from the dorsal aorta, distanced by the length of one somite, migrate dorsally each led by a tip cell and followed by stalk cells[20]
In venous intersegmental vessels (ISVs), the rate of proliferation is increased compared to aISVs, with a 46% fraction of two mitotic events in vISVs (Figure 1 E, Adapted Kolmogorov-Smirnov test, see methods, null test for frequency of mitosis in aISV vs vISV p

Summary

Introduction

The formation of a functional network of blood vessels with precisely controlled hierarchy and morphology is a crucial process during embryogenesis, development and disease progression. All blood vessels derive from angiogenesis, a process that entails the tight coordination of several endothelial cell (EC) behaviors including migration, proliferation and lumen formation[1,2,3]. As most studies investigated tip and stalk cell processes in the initial sprouting process as well as during the establishment of the primitive plexus, a detailed understanding of quantitative endothelial dynamics in vascular remodelling is lacking. To develop new models that predict the cellular behaviors that control vascular remodelling and hierarchical vascular patterning, a detailed quantitative characterization of EC dynamics and vascular morphology in this context will be required

Methods

Results

Conclusion