title: Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo.
abstract: How vascular tubes build, maintain and adapt continuously perfused lumens to meet local metabolic needs remains poorly understood. Recent studies showed that blood flow itself plays a critical role in the remodelling of vascular networks, and suggested it is also required for the lumenization of new vascular connections. However, it is still unknown how haemodynamic forces contribute to the formation of new vascular lumens during blood vessel morphogenesis. Here we report that blood flow drives lumen expansion during sprouting angiogenesis in vivo by inducing spherical deformations of the apical membrane of endothelial cells, in a process that we have termed inverse blebbing. We show that endothelial cells react to these membrane intrusions by local and transient recruitment and contraction of actomyosin, and that this mechanism is required for single, unidirectional lumen expansion in angiogenic sprouts. Our work identifies inverse membrane blebbing as a cellular response to high external pressure. We show that in the case of blood vessels such membrane dynamics can drive local cell shape changes required for global tissue morphogenesis, shedding light on a pressure-driven mechanism of lumen formation in vertebrates.
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.|Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Véronique
authors.initials: V
authors.lastname: Gebala
authors.affiliation: Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Russell
authors.initials: R
authors.lastname: Collins
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Geudens
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.|Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan.
authors.forename: Li-Kun
authors.initials: LK
authors.lastname: Phng
authors.affiliation: Integrative Vascular Biology Laboratory, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.|Vascular Patterning Laboratory, Vesalius Research Center, VIB, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany.|Berlin Institute of Health (BIH), Berlin, Germany.
authors.forename: Holger
authors.identifier: http://orcid.org/0000-0002-3030-0384
authors.initials: H
authors.lastname: Gerhardt
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D012039:Regional Blood Flow; D059008:Time-Lapse Imaging; D015027:Zebrafish
chemical_list: D008164:Luminescent Proteins; D000205:Actomyosin