Evidence of Hypoxia Signaling and Endothelial Activation in Migraine: Relationships Between HIF-1α, VEGF-A, and Arginine Metabolism

Background/Objectives: Migraine is a common neurovascular disorder associated with substantial disability. Increasing evidence suggests that hypoxia-related signaling, endothelial dysfunction, and nitric oxide metabolism contribute to its pathophysiology. This study investigated the relationships between hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor A (VEGF-A), and arginine pathway metabolites in chronic migraine. Methods: In this observational study, fasting ethylenediaminetetraacetic acid (EDTA) plasma samples were obtained from 28 patients with chronic migraine and 28 healthy controls. Arginine, citrulline, and ornithine concentrations were quantified by liquid chromatography–tandem mass spectrometry, whereas HIF-1α and VEGF-A were measured using enzyme-linked immunosorbent assays. Group comparisons, receiver operating characteristic analyses, and Firth penalized logistic regression models were performed. Results: Patients with chronic migraine exhibited significantly higher VEGF-A and HIF-1α concentrations than controls (both FDR-adjusted p ≤ 0.001). VEGF-A demonstrated excellent discrimination of migraine status (AUC = 0.973), whereas HIF-1α showed good discriminatory performance (AUC = 0.794). The arginine-to-citrulline ratio was higher (FDR-adjusted p = 0.032) and ornithine concentrations were lower (FDR-adjusted p = 0.043) in migraine patients. In multivariable analyses, VEGF-A (OR = 14.46), HIF-1α (OR = 5.83), and ornithine (OR = 0.28) remained independently associated with migraine status. Conclusions: Chronic migraine was associated with elevated circulating HIF-1α and VEGF-A concentrations together with alterations in arginine metabolism. These exploratory findings suggest that hypoxia-responsive signaling, endothelial activation, and nitric oxide-related metabolic pathways may represent interconnected biological processes associated with chronic migraine. Larger longitudinal and externally validated studies are required to confirm these observations and clarify their potential clinical relevance.