Mechanobiological Regulation of Endothelial Vascularization after Myocardial Infarction: Matrix Mechanics, Hydrogels Strategies and Applications

Abstract

Myocardial infarction (MI) triggers a wound-healing cascade that restores structural integrity but reshapes the cardiac mechanical microenvironment. The transition from compliant, healthy myocardium to stiff, fibrotic scar tissue creates biomechanical barriers that impede neovascularization and contribute to heart failure progression. These biomechanical cues regulate endothelial fate decisions, including migration, proliferation, branching, and lumen formation, and thus influence neovascularisation and perfusion recovery. This review addresses the mechanobiological principles governing endothelial cell behaviours and their translation into biomaterials-based strategies for cardiac regeneration or disease modelling. We first characterize the pathological remodelling cascade following MI, detailing the compositional and architectural shifts from healthy to infarcted myocardium. We then summarize how mechanical properties such as stiffness, viscoelastic stress relaxation, porosity, anisotropy, and degradability function as active regulators of endothelial activation, migration, junctional stability, and morphogenesis and ultimately angiogenesis in two- and three-dimensional environments. Subsequently, we evaluate various hydrogel platforms and tuning strategies, outlining how specific base composition, crosslinking chemistry, and network architecture are leveraged to modulate mechanical cues. Building on these mechanistic insights, we review hydrogel-based in vitro vascular models that emulate aspects of the post-infarct myocardium, including self-assembled endothelial-stromal networks, macroporous and granular scaffolds, organ-on-chip platforms with perfused microvessels, and 3D bioprinting approaches. Finally, we discuss limitations in decoupling mechanical from biochemical and architectural cues and in assessing vascular integration, perfusion, and functional outcomes in vivo. Together, this review highlights design principles for selecting and tuning matrix mechanics in biomaterial platforms aimed at supporting endothelial-driven revascularization of infarcted myocardium.