The extracellular matrix (ECM) plays a crucial role in angiogenesis beyond its traditional structural functions. It modulates angiogenic signaling, influences receptor activation, and controls cellular behaviors, contributing to the formation, maturation, and stabilization of vascular networks. The ECM interacts with various angiogenic factors and serves as a reservoir for bioactive molecules, highlighting its importance in both health and disease. The ECM's dynamic properties, including its composition, organization, and mechanical properties, regulate angiogenic signaling and processes in endothelial cells. Key ECM components, such as collagen, fibronectin, and laminin, are essential for vascular development and function. The ECM also facilitates biochemical signaling and mechanical transduction, influencing endothelial cell behavior and vascular morphogenesis. Growth factor (GF) signaling and integrin-mediated mechanotransduction are critical for angiogenesis, with VEGF-A being a master regulator. The ECM's interaction with GFs and integrins enables coactivation crosstalk, enhancing angiogenic signaling. The ECM's mechanical properties, such as stiffness, significantly influence cellular behavior, including adhesion, proliferation, and migration. Designer biomaterials that mimic the ECM's properties are being developed to engineer vascularized tissues and improve therapeutic outcomes. These materials aim to replicate the ECM's complex functionalities, including its ability to regulate GF signaling and cell mechanosensing. The ECM's role in wound healing and tumor vascularization is also critical, with its composition and organization affecting angiogenesis and vascular stability. Challenges remain in fully replicating the ECM's properties in biomaterials, but advances in synthetic biomimetic hydrogels and 3D bioprinting are enabling more accurate models of the ECM. The ECM's dynamic interactions with cells and growth factors are essential for both physiological and pathological angiogenesis, highlighting the need for further research to develop effective therapeutic interventions.The extracellular matrix (ECM) plays a crucial role in angiogenesis beyond its traditional structural functions. It modulates angiogenic signaling, influences receptor activation, and controls cellular behaviors, contributing to the formation, maturation, and stabilization of vascular networks. The ECM interacts with various angiogenic factors and serves as a reservoir for bioactive molecules, highlighting its importance in both health and disease. The ECM's dynamic properties, including its composition, organization, and mechanical properties, regulate angiogenic signaling and processes in endothelial cells. Key ECM components, such as collagen, fibronectin, and laminin, are essential for vascular development and function. The ECM also facilitates biochemical signaling and mechanical transduction, influencing endothelial cell behavior and vascular morphogenesis. Growth factor (GF) signaling and integrin-mediated mechanotransduction are critical for angiogenesis, with VEGF-A being a master regulator. The ECM's interaction with GFs and integrins enables coactivation crosstalk, enhancing angiogenic signaling. The ECM's mechanical properties, such as stiffness, significantly influence cellular behavior, including adhesion, proliferation, and migration. Designer biomaterials that mimic the ECM's properties are being developed to engineer vascularized tissues and improve therapeutic outcomes. These materials aim to replicate the ECM's complex functionalities, including its ability to regulate GF signaling and cell mechanosensing. The ECM's role in wound healing and tumor vascularization is also critical, with its composition and organization affecting angiogenesis and vascular stability. Challenges remain in fully replicating the ECM's properties in biomaterials, but advances in synthetic biomimetic hydrogels and 3D bioprinting are enabling more accurate models of the ECM. The ECM's dynamic interactions with cells and growth factors are essential for both physiological and pathological angiogenesis, highlighting the need for further research to develop effective therapeutic interventions.