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Tissue regeneration necessitates rapid and mature angiogenesis, while insufficient vascularization along with tissue implantation hinders the great potential applications. Endothelial cells (ECs) and bone marrow mesenchymal cells (BMSCs) are responsible for the angiogenesis in preparing bone tissue. Herein, we proposed the realization of the angiogenesis by co-culturing ECs and BMSCs within an injectable multi-crosslinked double-network (DN) hydrogel, composed of glycol chitosan (GC)/benzaldehyde-capped poly (ethylene oxide) (OHC-PEO-CHO) and calcium alginate (Alg). The hydrogel is crosslinked by dynamic interplay allowing the encapsulation, migration and proliferation of the cells. The hydrogel is capable to carry vascular endothelial growth factor (VEGF) with prolonging action within the matrix to effectively regulate the cell behavior. Co-existence of ECs and BMSCs with the VEGF within the hydrogel-based extracellular matrix (ECM) plays a key role in mediating the formation of a mature vascular structure with endothelium and pericyte. The neovascularization is closely related with the VEGF/VEGFR2/ERK signaling pathway. The finding indicates the direction toward future vascularized tissue regeneration by using a hydrogel-based scaffold with adjustable microenvironment by incorporation of functional growth factors. [Display omitted] • Injectable, multi-crosslinked double-network hydrogel prolongs the effect of VEGF. • Prolonged effect of VEGF enhances early angiogenesis. • The EC-BMSC 3D co-culture system could realize functional blood vessel formation. • The above process may be regulated through VEGF/VEGFR2/ERK signaling pathway. [ABSTRACT FROM AUTHOR]