Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks

Abstract

Sprouting angiogenesis is an essential vascularisation 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 polarise and migrate in response to flow-induced wall shear stress (WSS). However, the question of how the presence of erythrocytes (well-known as RBCs) and their haemodynamics impact affects 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 depletion, 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. SummaryRecent studies demonstrate that during sprouting angiogenesis, blood flow provides crucial hydrodynamic cues (e.g. wall shear stress) for the remodelling of primitive plexuses towards a functional network. Notwithstanding, the role of RBCs in this process remains poorly understood. We report on the inherent heterogeneity of RBC perfusion within primitive vasculatures, and uncover a strong association between RBC depletion and vessel regression. Our work indicates the essential role of RBC dynamics in the establishment of regional WSS differences driving vascular remodelling. The RBC-driven process of pruning cell-depleted vessels not only importantly contributes to the optimal patterning of vascular networks during development, but also provides a remodelling mechanism to support clinical findings of microangiopathic complications associated with impaired RBC deformability in diseases such as diabetes mellitus and hypertension.