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Emergent mechanical control of vascular morphogenesis.

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posted on 2023-08-15, 08:51 authored by Jordan Whisler, Somayeh Shahreza, Karin Schlegelmilch, Nil Ege, Yousef Javanmardi, Andrea Malandrino, Ayushi Agrawal, Alessandro Fantin, Bianca Serwinski, Hesham Azizgolshani, Clara Park, Victoria Shone, Olukunle O Demuren, Amanda Del Rosario, Vincent L Butty, Natalie Holroyd, Marie-Charlotte Domart, Steven Hooper, Nicolas Szita, Laurie A Boyer, Simon Walker-Samuel, Boris Djordjevic, Graham K Sheridan, Lucy Collinson, Fernando Calvo, Christiana Ruhrberg, Erik Sahai, Roger Kamm, Emad Moeendarbary
Vascularization is driven by morphogen signals and mechanical cues that coordinately regulate cellular force generation, migration, and shape change to sculpt the developing vascular network. However, it remains unclear whether developing vasculature actively regulates its own mechanical properties to achieve effective vascularization. We engineered tissue constructs containing endothelial cells and fibroblasts to investigate the mechanics of vascularization. Tissue stiffness increases during vascular morphogenesis resulting from emergent interactions between endothelial cells, fibroblasts, and ECM and correlates with enhanced vascular function. Contractile cellular forces are key to emergent tissue stiffening and synergize with ECM mechanical properties to modulate the mechanics of vascularization. Emergent tissue stiffening and vascular function rely on mechanotransduction signaling within fibroblasts, mediated by YAP1. Mouse embryos lacking YAP1 in fibroblasts exhibit both reduced tissue stiffness and develop lethal vascular defects. Translating our findings through biology-inspired vascular tissue engineering approaches will have substantial implications in regenerative medicine.

Funding

Crick (Grant ID: CC2040, Grant title: Sahai CC2040) Crick (Grant ID: CC1076, Grant title: STP Electron Microscopy) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology) European Research Council (Grant ID: 101019366 - CAN_ORGANISE, Grant title: ERC 101019366 - CAN_ORGANISE)

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