Hepatic cavernous hemangioma decellularized extracellular matrix/GelMA composite hydrogel promotes angiogenesis via the ITGA9–FAK–ERK1/2 axis

Effective angiogenesis is crucial for tissue engineering and regenerative medicine. However, current strategies such as growth factor or endothelial cell (EC) delivery often face challenges in inducing stable and efficient vascularization. Inspired by mimicking matrix composition and physical architecture of vascular hyperplastic tissues, we developed a novel composite hydrogel composed of decellularized extracellular matrix from human hepatic cavernous hemangioma (HCH dECM) and gelatin methacryloyl (GelMA) to promote angiogenesis for tissue engineering applications. The HCH dECM/GelMA hydrogel exhibited improved mechanical stability, uniform porosity, and retention of pro-angiogenic basement membrane components, as confirmed by proteomic and biomechanical analyses. In vitro, the hydrogel significantly enhanced the viability, proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs), outperforming Matrigel in key morphological metrics. In a mouse subcutaneous implantation model, the HCH dECM/GelMA hydrogel robustly induced vascularization by recruiting host endothelial cells, as evidenced by increased CD31 + and α-SMA + areas. Mechanistic investigations revealed that the hydrogel upregulates integrin alpha 9 (ITGA9), activating the FAK–ERK1/2 signaling pathway and enhancing the expression of angiogenic cytokines such as VEGFA. Knockdown of ITGA9 abolished these pro-angiogenic effects, confirming the essential role of the ITGA9–FAK–ERK1/2 axis. This work presents a human-derived, bioactive hydrogel with significant potential for vascular regeneration and clinical translation.