Molecular control of endothelial cell behaviour during blood vessel morphogenesis

Abstract

New blood vessel morphogenesis by angiogenic sprouting requires the highly coordinated and dynamic control of endothelial cell (EC) behaviour. Recent studies shed new light on the complex molecular mechanisms controlling EC behaviour in sprouting vessels, providing important insights into key biological processes, such as branching morphogenesis, tubulogenesis and mechanotransduction. Angiogenic branching involves the hierarchical sprouting of leading endothelial 'tip cells' (TCs) and trailing 'stalk cells' (SCs). Signalling via vascular endothelial growth factor receptor 2 (VEGFR2) and VEGFR3 promotes TC behaviour, whereas expression of the decoy receptor, VEGFR1, limits TC formation. Activation of Notch signalling in SCs negatively regulates VEGFR function to repress TC behaviour and maintain the hierarchical organization of sprouting TCs and SCs. Consequently, the cell-type-specific transcriptional control of Notch ligand expression or the post-translational control of Notch activity act as key control points that determine TC and SC fate. Vascular tubulogenesis is an essential aspect of angiogenic sprouting that generates a blood vessel lumen capable of carrying blood flow. Emerging evidence indicates that vascular lumen formation is a multistep process that is initiated by the acquisition of EC apicobasal polarity and is regulated by cell–matrix interactions, as well as partitioning defective 3 (PAR3) and VEGFR signalling. Increasing evidence shows that multiple signalling pathways have common roles in the guidance of both migrating axonal growth cones and ECs. In particular, signalling mediated by the neuronal guidance cues uncoordinated 5 homologue B (UNC5B), Roundabout homologue 4 (ROBO4), plexin D1, neuropilins, ephrin B2 and ephrin receptor B4 (EPHB4) has key roles in vascular development. Post-transcriptional control of blood vessel formation by microRNAs is involved in the fine-tuning of pro-angiogenic signalling during development, disease and in response to mechanical cues, such as blood flow. Furthermore, recent studies identify important post-translational mechanisms that control VEGFR membrane trafficking and signalling during angiogenesis in vivo.