Angiopoietin‐2 associates with poor prognosis in Moyamoya angiopathy

Abstract

AbstractObjectiveMoyamoya angiopathy (MA) is a rare cerebrovascular disorder characterized by recurrent ischemic/hemorrhagic strokes due to progressive occlusion of the intracranial carotid arteries. The lack of reliable disease severity biomarkers led us to investigate molecular features of a Caucasian cohort of MA patients.MethodsThe participants consisted of 30 MA patients and 40 controls. We measured cerebrospinal fluid (CSF) levels of angiogenic/inflammatory factors (ELISA). We then applied quantitative real‐time PCR on cerebral artery specimens for expression analyses of angiogenic factors. By an immunoassay based on microfluidic technology, we examined the potential correlations between plasma protein expression and MA clinical progression. A RNA interference approach toward Ring Finger Protein 213 (RNF213) and a tube formation assay were applied in cellular model.ResultsWe detected a statistically significant (p < 0.000001) up‐regulation of Angiopoietin‐2 (Ang‐2) in CSF and stenotic middle cerebral arteries (RQ >2) of MA patients compared to controls. A high Ang‐2 plasma concentration (p = 0.018) was associated with unfavorable outcome in a subset of MA patients. ROC curve analyses indicated Ang‐2 as diagnostic CSF biomarker (>3741 pg/mL) and prognostic plasma biomarker (>1162 pg/mL), to distinguish stable‐from‐progressive MA. Consistently, MA cellular model showed a significant up‐regulation (RQ >2) of Ang‐2 in RNF213 silenced condition.InterpretationOur results pointed out Ang‐2 as a reliable biomarker mirroring arterial steno‐occlusion and vascular instability of MA in CSF and blood, providing a candidate factor for patient stratification. This pilot study may pave the way to the validation of a biomarker to identify progressive MA patients deserving a specific treatment path.