Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks.

Qi Zhou,Tijana Perovic,Timm Krüger,Lowell T Edgar,Peter R Hoskins,Ines Fechner,Miguel O Bernabeu,Holger Gerhardt

doi:10.1098/rsif.2021.0113

Abstract

Sprouting angiogenesis is an essential vascularization mechanism consisting of sprouting and remodelling. The remodelling phase is driven by rearrangements of endothelial cells (ECs) within the post-sprouting vascular plexus. Prior work has uncovered how ECs polarize and migrate in response to flow-induced wall shear stress (WSS). However, the question of how the presence of erythrocytes (widely known as red blood cells (RBCs)) and their impact on haemodynamics affect vascular remodelling remains unanswered. Here, we devise a computational framework to model cellular blood flow in developmental mouse retina. We demonstrate a previously unreported highly heterogeneous distribution of RBCs in primitive vasculature. Furthermore, we report a strong association between vessel regression and RBC hypoperfusion, and identify plasma skimming as the driving mechanism. Live imaging in a developmental zebrafish model confirms this association. Taken together, our results indicate that RBC dynamics are fundamental to establishing the regional WSS differences driving vascular remodelling via their ability to modulate effective viscosity.

Highlights

Sprouting angiogenesis is an essential vascularization mechanism and consists of two well-differentiated phases: sprouting and remodelling [1,2]
In line with our previous findings on wall shear stress (WSS)-modulated endothelial cells (ECs) migration, we argue here that red blood cells (RBCs) hypoperfusion constitutes a mechanism for the enhancement of local WSS differences driving vascular remodelling
We speculate that vascular remodelling driven by the principle of removing RBC-poor vessels from the primitive vasculature will lead to a network layout that avoids portions of the tissue being vascularized but with poorly oxygenated blood

Summary

Introduction

Sprouting angiogenesis is an essential vascularization mechanism and consists of two well-differentiated phases: sprouting and remodelling [1,2]. Studies in various animal models have shown that blood flow provides mechanical cues to drive vascular remodelling (e.g. chick embryo [6], mouse yolk sac [7,8], mouse aortic arch [9], zebrafish embryo [4,10,11,12] and mouse retina [4]) These studies have uncovered multiple molecular regulators of EC response to blood shear stress, such as VEGF [13], Wnt [14], Notch [15,16], TGFβ/BMP [17,18,19], DACH1 [20] and KLF2 [21,22]

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Discussion

Conclusion