Temporal dynamics of angiogenesis: the emerging role of mechanoregulated pathways

Controlling the formation of new blood vessels, i.e. angiogenesis, is a critical challenge for the success of regenerative medicine. The development of effective strategies is hindered by our incomplete understanding of the dynamic mechanisms involved. During physiological angiogenesis, endothelial cells ensure the formation of a functional vascular network by organizing into phenotypic patterns of tip and stalk cells, as mediated by cell-cell signaling communication. While fundamental research identified the major signaling pathways involved in the tip-stalk selection process, recent studies have highlighted the importance of the temporal dynamics of these signaling pathways in determining the final vascular network topology. In this review, we discuss research studies where synergistic approaches between experimental and computational methods led to a renovated understanding of angiogenesis by revealing new temporal regulators of tip-stalk selection. Next, we present increasing evidence suggesting that mechanical cues, such as extracellular matrix stiffness, cyclic strain, and shear stress, are potential temporal regulators of the dynamics of tip-stalk selection and angiogenesis. Future research focused on this promising direction could enable the development of novel approaches that leverage temporal variations of mechanical cues to steer blood vessel growth.