Gelatin‐Mediated Vascular Self‐Assembly via a YAP‐MMP Signaling Axis

Abstract Tissue self‐assembly relies on the interplay between structural cues imparted by the extracellular matrix (ECM) and instructive chemical factors that guide cellular signaling pathways. Here, it is reported that endothelial cell‐laden gelatin‐based hydrogels with optimized mechanical and chemical properties facilitate de novo vasculogenesis and recruitment of endogenous blood vessels in vivo. It is demonstrated that these engineered matrices, with tailored viscoelastic features and stiffness, drive vascular self‐assembly in a yes‐associated protein (YAP) mechanosensing‐dependent manner through integrin alpha V beta 3 (αvβ3) and matrix metalloproteinase 2 activity (MMP2). This research highlights how the ECM, in the form of gelatin‐based hydrogels with adjustable stress relaxation rates, drives vascular morphogenesis in the absence of growth factor supplementation, lending to a minimalistic platform for discretizing features of the microenvironment niche. Collectively, these results demonstrate a testbed that enables mechanistic evaluation of morphogenetic processes. Specifically, the results show how mechanical cues impact signaling pathways that modulate vascular remodeling, a critical tissue engineering paradigm needed for the translational application of vascularized grafts for regenerative medicine applications.