The phoenixin-14/GPR173 Axis enhances post-stroke angiogenesis through ETS1-mediated VEGF signaling

Intracerebral hemorrhage (ICH) contributes to poor neurological outcomes by interfering with angiogenesis and disrupting important signaling pathways. Through ETS1-mediated vascular endothelial growth factor (VEGF) signaling, this work examines how the phoenixin-14/GPR173 axis promotes post-stroke angiogenesis. According to Western blot analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, blood phoenixin-14 levels and cortical GPR173 expression were considerably lower in a mouse ICH model than in sham controls. In addition to increasing serum VEGF-A and VEGF receptor-2 expression, administering two doses of phoenixin-14 (5 nmol and 10 nmol) improved neurological function, decreased cerebral edema, and raised cortical microvessel density in a dose-dependent manner. Hemin-treated human brain microvascular endothelial cells showed reduced levels of phoenixin-14 and GPR173 in vitro, while phoenixin-14 treatment increased the expression of VEGF-A and VEGF receptor-2, restored cell viability, and encouraged tube formation. Phoenixin-14 also elevated the phosphorylation of a transcription factor called ETS1, and its mechanistic function was confirmed when ETS1 knockdown eliminated the angiogenic and VEGF-inducing effects of phoenixin-14. These results show that via ETS1-mediated VEGF signaling, the phoenixin-14/GPR173 axis promotes post-stroke angiogenesis, indicating a possible therapeutic target for ICH recovery.