Matrix deformations around angiogenic sprouts correlate to sprout dynamics and suggest pulling activity
| Autor: | Peter Carmeliet, Marie-Mo Vaeyens, Maarten B. J. Roeffaers, Tommy Heck, Christian Steuwe, Hans Van Oosterwyck, Alvaro Jorge-Peñas, Jorge Barrasa-Fano |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
collagen Cancer Research Physiology Angiogenesis pulling forces extracellular matrix Clinical Biochemistry Neovascularization Physiologic Matrix (biology) confocal microscopy Extracellular matrix 03 medical and health sciences Mechanobiology 0302 clinical medicine cellular forces Humans Computer Simulation sprouting angiogenesis Mechanotransduction Cytoskeleton mechanotransduction Sprouting angiogenesis Chemistry Dynamics (mechanics) Models Cardiovascular Endothelial Cells cytoskeleton mechanobiology Extracellular Matrix image processing 030104 developmental biology 030220 oncology & carcinogenesis in vitro model Biophysics endothelial invasion computer model |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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