The Notch signalling pathway is crucial to many developmental processes, including angiogenesis, where it regulates the differentiation of endothelial cells into tip and stalk cells. Notch signalling is mediated by a Notch ligand (Delta-like 1, Delta-like 4 or Jagged 1) presented on a ‘sender’ cell binding to its receptor (Notch 1-4) on an adjacent ‘receiving’ cell. Subsequent cleavage and endocytosis of the Notch extracellular domain (NECD) into the receiving cell requires remodelling of the extracellular matrix (ECM). However, how the biomechanical properties of the ECM regulate this process is not known. In this study (Kretschmer et al., 2023), Stefan Zahler and colleagues grow endothelial cells on PDMS substrates of differing stiffness to investigate the effect of ECM stiffness on Notch signalling. Here, they find that Notch signalling inversely correlates with ECM stiffness; ‘softer’ substrates result in increased Notch activity. The authors also investigate the activation of integrin β1, since integrins are known to interact with the ECM. Similarly to Notch, increased levels of activated integrin β1 are seen on softer substrates. Interestingly, this activation is decreased by inhibition of Notch cleavage, suggesting that Notch signalling may act upstream of integrin β1 in a mechanosignalling context. Taken together, these data suggest that Notch signalling is regulated by ECM stiffness and thus may impact endothelial differentiation.
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