Tissue engineering is thought to the most promising strategy to develop successful small diameter vascular grafts (SDVG) to meet clinical demand. The introduction of natural substances into the SDVG made from synthetic biomaterials can improve the biocompatibility to promote the regeneration of SDVG in vivo. Due to that natural materials from different sources may have property deviation, it is vital to determine the source of natural materials to optimize SDVG fabrication for tissue engineering applications. In this study, bioactive SDVGs were prepared via coating of heparin-modified poly-(ε-caprolactone) scaffolds with a precursor solution containing vascular extracellular matrix (VECM) components and subsequent in situ gelation. The mechanical properties, degradation behaviors, and morphologies of the SDVGs were thoroughly characterized and evaluated. Cell experiments demonstrated the in vitro tissue specificity of the VECM that could promote the proliferation of endothelial cells better than skin-derived collagen. Furthermore, three types of SDVGs, SDVGs with blank hydrogel, SDVGs with skin-derived collagen, and SDVGs with vascular extracellular matrix (VECM-SDVGs), were implanted into the abdominal aorta of rats for one month. The explanted SDVGs were then comprehensively evaluated using hematoxylin and eosin, Masson, von Kossa staining, and immunohistochemical staining for CD31, α-SMA, and MHC. The results showed that the VECM-SDVGs showed the best endothelium regeneration, appropriate intima regeneration, and no calcification, indicating the in vivo specificity of the fabricated VECM-SDVGs. Thus, long-term implantation of VECM-SDVGs was performed. The results showed that a complete endothelial layer formed after 6 months of implantation, and the amount of contractile SMCs in the regenerative smooth muscle layer approached the amount of native aorta at the 12th month. Consequently, relying on vascular tissue specificity, VECM-SDVGs can modulate the regenerative behavior of the implanted SDVGs in vivo to achieve satisfactory vascular regeneration both in short- and long-term implantation.Copyright © 2022 Elsevier B.V. All rights reserved.