YAP/TAZ drives Notch and angiogenesis mechanoregulation in silico

• Published in: NPJ systems biology and applications Vol. 10; no. 1; pp. 116 - 16
• Main Authors: Passier, Margot, Bentley, Katie, Loerakker, Sandra, Ristori, Tommaso
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/553/2696; 639/166/985; Adaptor Proteins, Signal Transducing - metabolism; Angiogenesis; Bioinformatics; Biomedical and Life Sciences; Cardiovascular system; Computational Biology/Bioinformatics; Computer Appl. in Life Sciences; Computer Simulation; Cytoskeleton; Cytoskeleton - metabolism; Endothelial cells; Endothelial Cells - metabolism; Extracellular matrix; Humans; Life Sciences; Mathematical models; Mechanotransduction, Cellular - physiology; Models, Biological; Neovascularization, Physiologic - physiology; Receptors, Notch - metabolism; Signal transduction; Signal Transduction - physiology; Systems Biology; Transcription Factors - genetics; Transcription Factors - metabolism; YAP-Signaling Proteins - genetics; YAP-Signaling Proteins - metabolism; Yes-associated protein
• ISSN: 2056-7189; 2056-7189
• DOI: 10.1038/s41540-024-00444-3

Endothelial cells are key players in the cardiovascular system. Among other things, they are responsible for sprouting angiogenesis, the process of new blood vessel formation essential for both health and disease. Endothelial cells are strongly regulated by the juxtacrine signaling pathway Notch. Recent studies have shown that both Notch and angiogenesis are influenced by extracellular matrix stiffness; however, the underlying mechanisms are poorly understood. Here, we addressed this challenge by combining computational models of Notch signaling and YAP/TAZ, stiffness- and cytoskeleton-regulated mechanotransducers whose activity inhibits both Dll4 (Notch ligand) and LFng (Notch-Dll4 binding modulator). Our simulations successfully mimicked previous experiments, indicating that this YAP/TAZ-Notch crosstalk elucidates the Notch and angiogenesis mechanoresponse to stiffness. Additional simulations also identified possible strategies to control Notch activity and sprouting angiogenesis via cytoskeletal manipulations or spatial patterns of alternating stiffnesses. Our study thus inspires new experimental avenues and provides a promising modeling framework for further investigations into the role of Notch, YAP/TAZ, and mechanics in determining endothelial cell behavior during angiogenesis and similar processes.