Time to branch? Endothelial cell dynamics regulating vascular patterning


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Holger Gerhardt
Cancer Research UK London Research Institute, UK

Abstract

Blood vessel patterning involves the iterations of sprout initiation, elongation, anastomosis, lumen formation and stabilization. Endothelial cells concurrently migrate, divide, select dynamic phenotypes and rearrange positions to allow organized branching morphogenesis. How exactly the cells orchestrate their behaviour remains poorly understood. Our recent work identified a regulatory network of VEGF-VEGFR and Dll4/Notch signalling as a key mechanism of pattern generation. Mosaic analysis in zebrafish and embryoid body sprouting assays illustrated a constant competition between cells for the leading tip cell position utilizing differential VEGFR levels. Computer simulations suggest that the coordination and timing of the competitive cell behaviour and Dll4/Notch signalling drives the angiogenic branching 'pattern generator'. Observations of emergent behaviour in computer simulations of pathological blood vessel growth driven by high VEGF levels, as in ischemia or tumour angiogenesis, now provide the first predictions for a mechanism of pathological vascular patterning, and possibly for organ specific branching adaptations. Studies into the dynamic regulation of Dll4 in vitro and in vivo indicate that high VEGF levels disrupt the 'salt-and-pepper' pattern of Dll4 underlying branching morphogenesis. Instead, high VEGF levels promote contiguous Dll4 expression in clusters of adjacent cells that synchronize their behaviour, fail to rearrange and thus form vessel dilation domains leading to tortuosity. We propose that changes in the behaviour of the VEGF-Dll4-Notch feedback loop determine whether to branch or to expand a vessel during angiogenesis.