Proteoglycans and glycosaminoglycans: critical regulators in angiogenesis, vasculogenesis, and vascularized tissue engineering.

Reconstruction of the microvascular network is essential for tissue regeneration and functional repair. However, inadequate vascularization remains an arduous challenge, hindering graft survival in wound healing and regenerative medicine. Although neovascularization and vascularized tissue engineering have received considerable attention, current investigations into the regulatory mechanisms of microvascular regeneration have primarily focused on intracellular signaling entities, leaving the extracellular molecular-level regulatory mechanisms unclear. Proteoglycans (PGs), ubiquitously distributed in the extracellular matrix and on cell membranes, consist of glycosaminoglycan (GAG) chains covalently linked to core proteins. Their spatiotemporal heterogeneity enables precise modulation of neovascularization; however, the structural complexity of PGs/GAGs obscures their mechanistic roles in vascular remodeling. This review systematically analyzes the regulatory roles of PGs/GAGs in the distinct phases of angiogenesis and vasculogenesis, which are two fundamental neovascularization processes. Additionally, we explored the emerging applications of PGs/GAGs in vascularized tissue engineering and regenerative medicine (VTERM), focusing on PG/GAG-functionalized biomaterials designed to mimic the native extracellular microenvironment and enhance specific signaling. This article critically evaluates the latest advances in optimizing these composite materials, and highlights the challenges associated with achieving spatiotemporal control over vascularization. By integrating profound molecular insights into innovative translational practices, this study establishes a theoretical framework for leveraging PGs/GAGs as multifunctional regulators in next-generation VTERM strategies.