This dataset contains the raw confocal images, AFM measurements, and RNAseq values used in the study "Dynamic matrix stiffening reprograms endothelial angiogenic remodeling via α2-integrin mechanotransduction". Data includes .nd2 files collected from confocal microscopy for collagen and nascent protein expression, force-indentation oscillatory force curves (10Hz) to characterize endothelial cell and collagen/hyaluronic acid hydrogel stiffness, and RNAseq of endothelial cells cultured in collagen/hyaluronic acid hydrogels. All imaging was performed on a Nikon AX-R Confocal microscope using Element software, while AFM measurements were performed on a Bruker Nanowizard V Bioscience system using SAA-SPH-1UM or NP-O10 cantilevers. Raw force and displacement data were exported directly from instrument software. These files enable full reproduction of the analysis.