Dopamine D2 Receptor Agonists as Modulators of VEGF-A-Driven Angiogenesis: Mechanisms, Clinical Evidence, and Translational Opportunities.

Angiogenesis mediated by vascular endothelial growth factor A (VEGF-A) is essential for physiological vascular remodeling but also drives pathological processes, including tumor growth, ocular neovascularization, and inflammation. Emerging evidence has revealed that dopamine D2 receptor (DRD2) activation is a key inhibitory pathway that counterbalances VEGF-A-dependent endothelial activation and vascular permeability. This review integrates current mechanistic insights into the effects of DRD2 agonists on endothelial signaling, focusing on their ability to suppress VEGF-A-induced proangiogenic signaling cascades. Preclinical and translational studies have demonstrated that DRD2 agonists attenuate aberrant angiogenesis, promote vascular normalization, and mitigate VEGF-A-induced vascular leakage in diverse pathological contexts, including malignancy, ovarian hyperstimulation syndrome, endometriosis, and inflammatory lung injury. Particular attention is given to the emerging model of tumor-derived VEGF-A inducing DRD2 expression within the tumor endothelium, establishing a reciprocal paracrine feedback loop with potential biomarker relevance. Finally, the clinical safety profile and pharmacologic repositioning of DRD2 agonists are evaluated, and priorities for translational research are outlined to refine dosing, scheduling, and patient selection strategies in precision antiangiogenic therapy.