Circulating angiogenic profiles in ischemic stroke and intracranial atherosclerosis (ICAD)
Background and Aims: Intracranial atherosclerotic disease (ICAD) carries high recurrence rates despite intensive medical management. Prior studies suggest anti-angiogenic circulating profiles may contribute to treatment failure. This exploratory study evaluated associations between pro- and anti-angiogenic factors and stroke patterns in ICAD, specifically comparing hemodynamic (borderzone) versus embolic presentations.  Methods: We conducted a cross-sectional analysis of 110 patients with severe ICAD (=70% stenosis) from four U.S. centers (2019-2023). Five circulating factors were measured: VEGF, VEGF-165b, HGF (pro-angiogenic), and endostatin, angiostatin (anti-angiogenic). Stroke patterns were classified as hemodynamic (borderzone/watershed, n=28) or non-hemodynamic (embolic/perforator, n=82) based on MRI. A Random Forest classifier was developed to identify biomarker patterns associated with stroke type, with feature importance analysis to determine relative contributions.  Results: The Random Forest model achieved 85% accuracy (AUC 0.87) in discriminating hemodynamic from non-hemodynamic strokes using 5-fold cross-validation. Feature importance analysis revealed anti-angiogenic factors as the strongest predictors: angiostatin (25.6% importance) and endostatin (21.5%), followed by pro-angiogenic factors VEGF (18.3%) and HGF (18.1%). Secondary analyses showed moderate associations with functional independence (AUC 0.71) but not cognitive scores. Exosomal microRNA pathway analysis revealed enrichment in pathways common to both neurovascular insufficiency and neurodegenerative processes, suggesting potential shared mechanisms between vascular and degenerative pathologies.  Conclusions: This hypothesis-generating study identifies differential expression of angiogenic factors associated with hemodynamic versus embolic stroke patterns in ICAD. The predominance of anti-angiogenic factors in predicting hemodynamic strokes suggests impaired collateral formation may contribute to watershed ischemia. These preliminary associations warrant prospective validation to determine whether anti-angiogenic profiles could identify ICAD patients at risk for hemodynamic compromise. Overall design: Blood samples were collected from patients with ICAD ischemia. Levels of five angiogenic factors were measured by ELISA and recorded. Exosomal mi-RNA expression profiles were measured and compared between patients with hemodynamic and non-hemodynamic patterns of stroke.