From the Translational and Stem Cell Research Laboratory on Stroke (J.-W.C., D.H.K., M.J.O.,Y.H.C., E.H.K., O.Y.B.), Samsung Medical Center, Seoul, Republic of Korea.
Department of Neurology (J.-W.C., G.-M.K., O.Y.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Stroke. 2018 Nov;49(11):2597-2604. doi: 10.1161/STROKEAHA.118.021888.
Background and Purpose- Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease characterized by progressive stenosis and negative remodeling of the distal internal carotid artery (ICA). We hypothesized that cav-1 (caveolin-1)-a protein that controls the regulation of endothelial vesicular trafficking and signal transduction-is associated with negative remodeling in MMD. Methods- We prospectively recruited 77 consecutive patients with MMD diagnosed via conventional angiography. Seventeen patients with intracranial atherosclerotic stroke and no RNF213 mutation served as controls. The outer distal ICA diameters were examined using high-resolution magnetic resonance imaging. We evaluated whether the degree of negative remodeling in the patients with MMD was associated with RNF213 polymorphism, cav-1 levels, or various clinical and vascular risk factors. We also investigated whether the derived factor was associated with negative remodeling at the cellular level using the tube formation and apoptosis assays. Results- The serum cav-1 level was lower in the patients with MMD than in the controls (0.47±0.29 versus 0.86±0.68 ng/mL; P=0.034). The mean ICA diameter was 2.48±0.98 mm for the 126 affected distal ICAs in patients with MMD and 3.84±0.42 mm for the asymptomatic ICAs in the controls ( P<0.001). After adjusting for confounders, cav-1 levels (coefficient, 1.018; P<0.001) were independently associated with the distal ICA diameter in patients with MMD. In vitro analysis showed that cav-1 downregulation suppressed angiogenesis in the endothelial cells and induced apoptosis in the smooth muscle cells. Conclusions- Our findings suggest that cav-1 may play a major role in negative arterial remodeling in MMD.
背景与目的- 烟雾病（MMD）是一种独特的脑血管闭塞性疾病，其特征为颈内动脉（ICA）远端进行性狭窄和负性重构。我们假设 cav-1（小窝蛋白-1）——一种控制内皮小泡转运和信号转导调节的蛋白——与 MMD 的负性重构有关。方法- 我们前瞻性招募了 77 例经常规血管造影诊断为 MMD 的连续患者。17 例颅内动脉粥样硬化性卒中且无 RNF213 突变的患者作为对照组。使用高分辨率磁共振成像检查远端 ICA 外径。我们评估了 MMD 患者的负性重构程度是否与 RNF213 多态性、cav-1 水平或各种临床和血管危险因素有关。我们还通过管形成和细胞凋亡测定研究了推导因子是否与细胞水平的负性重构有关。结果- MMD 患者的血清 cav-1 水平低于对照组（0.47±0.29 与 0.86±0.68ng/ml；P=0.034）。126 例 MMD 患者受累的远端 ICA 的平均 ICA 直径为 2.48±0.98mm，对照组无症状 ICA 的平均 ICA 直径为 3.84±0.42mm（P<0.001）。在调整混杂因素后，cav-1 水平（系数，1.018；P<0.001）与 MMD 患者的远端 ICA 直径独立相关。体外分析表明，cav-1 下调抑制了内皮细胞的血管生成，并诱导了平滑肌细胞的凋亡。结论- 我们的研究结果表明，cav-1 可能在 MMD 的动脉负性重构中起主要作用。
