Significance of Serum Angiopoietin-2 in Patients with Hemorrhage in Adult-Onset Moyamoya Disease

Abstract

Background. Moyamoya disease (MMD) is a progressive occlusive cerebrovascular disease that is characterized by abnormal angiogenesis at the base of the brain. This pathological abnormal angiogenesis is susceptible to disturbances, including spontaneous hemorrhage and vasogenic edema. However, the underlying mechanisms of pathological angiogenesis and occurrence of hemorrhage are unclear. Angiopoietins play a fundamental role in the pathophysiology of central nervous system disorders in angiogenesis. This study was aimed at examining whether angiopoietins are associated with formation of abnormal collateral vessels and the occurrence of hemorrhage in adult-onset moyamoya disease (HMMD). Methods. A total of 27 consecutive adult patients with HMMD were enrolled from June 2011 to May 2017. Serum levels of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) were examined by enzyme-linked immunosorbent assay. Patients with HMMD were compared with those with spontaneous hemorrhage (controls) and nonhemorrhagic-onset MMD (NHMMD). Results. Serum Ang-2 levels were significantly higher in patients with adult HMMD than in those with spontaneous hemorrhage and NHMMD. The ROC curve identified that a baseline serum Ang-2 level>1230 ng/ml may be associated with adult HMMD with 88.39% sensitivity and 70.37% specificity (area under the curve (AUC), 0.89; 95% CI, 0.808-0.973; P<0.001). Moreover, serum Ang-2 levels were significantly elevated in stages II, III, and IV. In subgroup analysis of a high and low degree of moyamoya vessels, serum Ang-2 levels were significantly higher in the high moyamoya vessel group than in the low moyamoya vessel group. Serum Ang-2 levels were also significantly higher in the low moyamoya vessel group compared with the control group. Serum Ang-1 levels were not significantly different among the groups. Conclusion. Increased serum Ang-2 levels may contribute to pathological abnormal angiogenesis and/or to the instability of vascular structure and function, thus causing brain hemorrhage in adult HMMD.

Bloody fluids located between the temporal muscle and targeted cerebral cortex affect the establishment of indirect collaterals in Moyamoya disease with surgical bypass: A case-control study

“…Previous studies confirmed that the VEGF levels were nearly identical to those in healthy cohorts, confirming an active neovascularization state in patients with MMD ( 7 ) despite decreased serum caveolin-1 concentrations associated with negative arterial remodeling ( 18 ). Increased serum angiopoietin-2 levels have been described ( 19 ), and angiopoietins contained in these fluids may facilitate vascular responses that regulate angiogenesis via an autocrine release in patients with MMD ( 20 ). Additionally, surgical bypass can elevate VEGF-A 165 a/b ratios in MMD and intracranial atherosclerotic disease ( 21 ).…”

The Progression of Pathophysiology of Moyamoya Disease

“…Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) levels in serum were higher in patients with MMD than in healthy controls. 44,60 Blecharz et al 14 Demonstrated that Ang-2, but not Ang-1, was significantly overexpressed in the intracranial artery of patients with MMD. Ang-2 mediated MMD cerebrovascular disintegration by weakening the EC barrier in an autocrine manner, and the destabilization of brain ECs could be partially restored by the inhibition of Ang-2 by exogenous administration of Ang-1.…”

Genetic and Proteomic Contributions to the Pathophysiology of Moyamoya Angiopathy and Related Vascular Diseases

“…The results obtained by the group may identify cerebral endothelial cells as a potential source of vessel-destabilizing factors, inducing plastic and unstable neovascularization and cerebrovascular disintegration in MA, mediated by the autocrine release of the pro-angiogenic cytokine ANG2, thereby elucidating a mechanism that may contribute to cerebrovascular hemorrhagic and ischemic events in MA. 190 Yu et al 191 showed that ANG2 may be involved in the pathophysiology of increased angiogenesis in adult hemorrhagic MA and may also be a prognostic factor of intracranial hemorrhage in adult MA patients. Infection is linked to Tie2 signaling disruption that is related to vascular leakage.…”