Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling
Abstract Blood vessel formation relies on biochemical and mechanical signals, particularly during sprouting angiogenesis when endothelial tip cells (TCs) guide sprouting through filopodia formation. The contribution of BMP receptors in defining tip-cell characteristics is poorly understood. Our stud...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07431-8 |
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| author | Christian Hiepen Mounir Benamar Jorge Barrasa-Fano Mar Condor Mustafa Ilhan Juliane Münch Nurcan Hastar Yannic Kerkhoff Gregory S. Harms Thorsten Mielke Benjamin Koenig Stephan Block Oliver Rocks Salim Abdelilah-Seyfried Hans Van Oosterwyck Petra Knaus |
| author_facet | Christian Hiepen Mounir Benamar Jorge Barrasa-Fano Mar Condor Mustafa Ilhan Juliane Münch Nurcan Hastar Yannic Kerkhoff Gregory S. Harms Thorsten Mielke Benjamin Koenig Stephan Block Oliver Rocks Salim Abdelilah-Seyfried Hans Van Oosterwyck Petra Knaus |
| author_sort | Christian Hiepen |
| collection | DOAJ |
| description | Abstract Blood vessel formation relies on biochemical and mechanical signals, particularly during sprouting angiogenesis when endothelial tip cells (TCs) guide sprouting through filopodia formation. The contribution of BMP receptors in defining tip-cell characteristics is poorly understood. Our study combines genetic, biochemical, and molecular methods together with 3D traction force microscopy, which reveals an essential role of BMPR2 for actin-driven filopodia formation and mechanical properties of endothelial cells (ECs). Targeting of Bmpr2 reduced sprouting angiogenesis in zebrafish and BMPR2-deficient human ECs formed fewer filopodia, affecting cell migration and actomyosin localization. Spheroid assays revealed a reduced sprouting of BMPR2-deficient ECs in fibrin gels. Even more strikingly, in mosaic spheroids, BMPR2-deficient ECs failed to acquire tip-cell positions. Yet, 3D traction force microscopy revealed that these distinct cell behaviors of BMPR2-deficient tip cells cannot be explained by differences in force-induced matrix deformations, even though these cells adopted distinct cone-shaped morphologies. Notably, BMPR2 positively regulates local CDC42 activity at the plasma membrane to promote filopodia formation. Our findings reveal that BMPR2 functions as a nexus integrating biochemical and biomechanical processes crucial for TCs during angiogenesis. |
| format | Article |
| id | doaj-art-f2a9f70940484362b7c3502173bf8c5a |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-f2a9f70940484362b7c3502173bf8c5a2025-01-12T12:35:44ZengNature PortfolioCommunications Biology2399-36422025-01-018112210.1038/s42003-024-07431-8Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signalingChristian Hiepen0Mounir Benamar1Jorge Barrasa-Fano2Mar Condor3Mustafa Ilhan4Juliane Münch5Nurcan Hastar6Yannic Kerkhoff7Gregory S. Harms8Thorsten Mielke9Benjamin Koenig10Stephan Block11Oliver Rocks12Salim Abdelilah-Seyfried13Hans Van Oosterwyck14Petra Knaus15Freie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63Freie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63KU Leuven, Department of Mechanical Engineering, Biomechanics section, Leuven, Celestijnenlaan 300 CKU Leuven, Department of Mechanical Engineering, Biomechanics section, Leuven, Celestijnenlaan 300 CFreie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63Universität Potsdam, Institute of Biochemistry and Biology, Karl-Liebknecht Strasse 24-25Freie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63Freie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63Universitätsmedizin, Johannes Gutenberg-Universität Mainz, Cell Biology Unit, Imaging Core Facility and the Research Center for Immune Intervention, Langenbeckstraße 1Max-Planck-Institute for Molecular Genetics, Microscopy & Cryo-Electron Microscopy, Ihnestraße 63-73Freie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63Freie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63Charité - Universitätsmedizin Berlin, Systemic Cell Dynamics, Charitéplatz 1Universität Potsdam, Institute of Biochemistry and Biology, Karl-Liebknecht Strasse 24-25KU Leuven, Department of Mechanical Engineering, Biomechanics section, Leuven, Celestijnenlaan 300 CFreie Universität Berlin, Institute for Chemistry and Biochemistry, Thielallee 63Abstract Blood vessel formation relies on biochemical and mechanical signals, particularly during sprouting angiogenesis when endothelial tip cells (TCs) guide sprouting through filopodia formation. The contribution of BMP receptors in defining tip-cell characteristics is poorly understood. Our study combines genetic, biochemical, and molecular methods together with 3D traction force microscopy, which reveals an essential role of BMPR2 for actin-driven filopodia formation and mechanical properties of endothelial cells (ECs). Targeting of Bmpr2 reduced sprouting angiogenesis in zebrafish and BMPR2-deficient human ECs formed fewer filopodia, affecting cell migration and actomyosin localization. Spheroid assays revealed a reduced sprouting of BMPR2-deficient ECs in fibrin gels. Even more strikingly, in mosaic spheroids, BMPR2-deficient ECs failed to acquire tip-cell positions. Yet, 3D traction force microscopy revealed that these distinct cell behaviors of BMPR2-deficient tip cells cannot be explained by differences in force-induced matrix deformations, even though these cells adopted distinct cone-shaped morphologies. Notably, BMPR2 positively regulates local CDC42 activity at the plasma membrane to promote filopodia formation. Our findings reveal that BMPR2 functions as a nexus integrating biochemical and biomechanical processes crucial for TCs during angiogenesis.https://doi.org/10.1038/s42003-024-07431-8 |
| spellingShingle | Christian Hiepen Mounir Benamar Jorge Barrasa-Fano Mar Condor Mustafa Ilhan Juliane Münch Nurcan Hastar Yannic Kerkhoff Gregory S. Harms Thorsten Mielke Benjamin Koenig Stephan Block Oliver Rocks Salim Abdelilah-Seyfried Hans Van Oosterwyck Petra Knaus Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling Communications Biology |
| title | Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling |
| title_full | Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling |
| title_fullStr | Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling |
| title_full_unstemmed | Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling |
| title_short | Endothelial tip-cell position, filopodia formation and biomechanics require BMPR2 expression and signaling |
| title_sort | endothelial tip cell position filopodia formation and biomechanics require bmpr2 expression and signaling |
| url | https://doi.org/10.1038/s42003-024-07431-8 |
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