Emergent mechanical control of vascular morphogenesis.

Area of Science:

• Developmental Biology
• Biomedical Engineering
• Mechanobiology

Background:

• Vascularization relies on morphogen signals and mechanical cues to guide cell behavior and shape the vascular network.
• The role of active mechanical property regulation by developing vasculature in achieving effective vascularization remains largely unexplored.

Purpose of the Study:

• To investigate the mechanics of vascularization by examining how tissue mechanical properties change during blood vessel development.
• To determine the cellular and molecular mechanisms underlying emergent tissue stiffening during vascular morphogenesis.
• To assess the role of fibroblast mechanotransduction and YAP1 signaling in regulating vascular mechanics and function.

Main Methods:

• Engineered tissue constructs comprising endothelial cells and fibroblasts were utilized to study vascularization mechanics.
• Measurements of tissue stiffness, cellular forces, and extracellular matrix (ECM) interactions were performed.
• Genetic manipulation, including the absence of YAP1 in fibroblasts, was employed in mouse models to investigate mechanotransduction pathways.

Main Results:

• Tissue stiffness significantly increases during vascular morphogenesis, correlating with enhanced vascular function.
• Contractile cellular forces from fibroblasts are critical for emergent tissue stiffening, working in synergy with ECM properties.
• Fibroblast-specific YAP1 signaling is essential for mechanotransduction, emergent tissue stiffening, and normal vascular function; its absence leads to reduced stiffness and lethal vascular defects in mouse embryos.

Conclusions:

• Developing vasculature actively regulates its mechanical properties, with tissue stiffening being a key emergent phenomenon.
• Fibroblast mechanotransduction, mediated by YAP1, plays a critical role in controlling vascular mechanics and development.
• These findings highlight the importance of mechanical regulation in vascularization and offer insights for regenerative medicine through bio-inspired tissue engineering.