Dopamine D2 receptor agonists modulate VEGF-A angiogenesis, offering therapeutic potential in cancer and ocular diseases

Angiogenesis, driven by vascular endothelial growth factor A (VEGF-A), is critical for physiological processes but also fuels pathological conditions like tumor growth, ocular neovascularization, and chronic inflammation. Current anti-VEGF therapies face limitations, including resistance and off-target effects. Emerging evidence points to dopamine D2 receptor (DRD2) activation as a novel mechanism to modulate VEGF-A-mediated angiogenesis, presenting a promising avenue for therapeutic intervention by targeting this distinct pathway.

This comprehensive review synthesized evidence from preclinical studies, clinical trials, and mechanistic investigations to elucidate the role of dopamine D2 receptor agonists in modulating VEGF-A-driven angiogenesis. The authors systematically analyzed existing literature, focusing on molecular mechanisms, the emerging DRD2-VEGF-A paracrine loop, and the clinical safety and repositioning potential of these compounds. The review aimed to identify translational opportunities for DRD2 agonists in various angiogenesis-dependent pathologies.

The review elucidated that DRD2 agonists directly inhibit VEGF-A signaling, thereby suppressing pathological angiogenesis. Key mechanisms include modulation of VEGF-A receptor expression, downstream signaling pathways like ERK1/2 and AKT, and direct effects on endothelial cell proliferation and migration. A significant finding is the proposed reciprocal paracrine feedback loop where tumor-derived VEGF-A induces DRD2 expression in tumor endothelium, creating a targetable vulnerability. This mechanism suggests DRD2 expression could serve as a predictive biomarker. Clinical evidence supports the anti-angiogenic effects of DRD2 agonists, with existing drugs demonstrating favorable safety profiles and potential for repositioning in conditions like cancer and ocular neovascularization. The synthesis of data highlights that DRD2 agonists can disrupt the pro-angiogenic microenvironment, offering a novel therapeutic strategy.

The review also identified DRD2 expression in tumor endothelium as a potential biomarker for predicting response to these therapies.