Blood vessels form a closed circulatory network that transports blood from the heart to peripheral tissues and back. Long-term vascular adaptation is mediated by angiogenesis, and the principal stages of this process have been systematically investigated, with particular emphasis on the microvascular bed and vessel sprouting. Angiogenesis is a fundamental adaptive process, tightly regulated by chemical, neural, and molecular mechanisms. Furthermore, the biological effects of several canonical regulators of vessel guidance, such as VEGF and bFGF, require precise regulation to ensure proper vascular network patterning and subsequent function. Emerging evidence suggests the need to adopt a broader perspective that incorporates new biological actors, such as the UNC5B (Uncoordinated-5 homolog b) receptor, a member of the Netrin family, which has been described as either pro- or anti-angiogenic depending on the specific vascular bed. However, the putative role and contribution of non-classical receptors, such as UNC5B, in the vascular patterning and endothelial stability via distinct intracellular signaling pathways have not been fully explored. Different forms of crosstalk among trophic mediators help maintain balanced angiogenic and barrier-stabilizing functions and a reparative microenvironment, which could be a potential therapeutic target depending on the vascular bed. Recent studies demonstrate that UNC5B function is shaped by tissue-specific molecular contexts, including ligand availability, co-receptor expression, and local signaling cues, positioning it as a context-dependent regulator of signaling balance. Transcriptomic analyses and experimental models reveal marked heterogeneity in UNC5B expression across endothelial subtypes, particularly in placental, retinal, and central nervous system vasculature, suggesting specialized roles in barrier maintenance and angiogenic fine-tuning.