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29.01.2020 | Brief Communication

Matrix deformations around angiogenic sprouts correlate to sprout dynamics and suggest pulling activity

Marie-Mo Vaeyens, Alvaro Jorge-Peñas, Jorge Barrasa-Fano, Christian Steuwe, Tommy Heck, Peter Carmeliet, Maarten Roeffaers, Hans Van Oosterwyck
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The online version of this article (https://​doi.​org/​10.​1007/​s10456-020-09708-y) contains supplementary material, which is available to authorized users.

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Angiogenesis is the formation of new blood vessels from the pre-existing vasculature. It is essential for normal tissue growth and regeneration, and also plays a key role in many diseases [Carmeliet in Nat Med 9:653–660, 2003]. Cytoskeletal components have been shown to be important for angiogenic sprout initiation and maintenance [Kniazeva and Putnam in Am J Physiol 297:C179–C187, 2009] as well as endothelial cell shape control during invasion [Elliott et al. in Nat Cell Biol 17:137–147, 2015]. The exact nature of cytoskeleton-mediated forces for sprout initiation and progression, however, remains poorly understood. Questions on the importance of tip cell pulling versus stalk cell pushing are to a large extent unanswered, which among others has to do with the difficulty of quantifying and resolving those forces in time and space. We developed methods based on time-lapse confocal microscopy and image processing—further termed 4D displacement microscopy—to acquire detailed, spatially and temporally resolved extracellular matrix (ECM) deformations, indicative of cell-ECM mechanical interactions around invading sprouts. We demonstrate that matrix deformations dependent on actin-mediated force generation are spatio-temporally correlated with sprout morphological dynamics. Furthermore, sprout tips were found to exert radially pulling forces on the extracellular matrix, which were quantified by means of a computational model of collagen ECM mechanics. Protrusions from extending sprouts mostly increase their pulling forces, while retracting protrusions mainly reduce their pulling forces. Displacement microscopy analysis further unveiled a characteristic dipole-like deformation pattern along the sprout direction that was consistent among seemingly very different sprout shapes—with oppositely oriented displacements at sprout tip versus sprout base and a transition zone of negligible displacements in between. These results demonstrate that sprout-ECM interactions are dominated by pulling forces and underline the key role of tip cell pulling for sprouting angiogenesis.

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