From the Department of Cell and Molecular Biology (T.H., S.J., U.L.) and Department of Medical Biochemistry and Biophysics, Division of Vascular Biology (C.B., E.R.), Karolinska Institute, Stockholm, Sweden; Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden (A.K., L.H., E.R., M.A.M., C.B.); EM Unit, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (B.R.J.); and Octapharma AB, Stockholm, Sweden (E.W.).
Arterioscler Thromb Vasc Biol. 2015 Feb;35(2):409-20. doi: 10.1161/ATVBAHA.114.304849. Epub 2014 Dec 4.
Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution, and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood-brain barrier function is less well understood. In this report, we explored the impact of the loss of VSMC in the Notch3(-/-) mouse on blood vessel integrity in the central nervous system.
Notch3(-/-) mice showed focal disruptions of the blood-brain barrier demonstrated by extravasation of tracers accompanied by fibrin deposition in the retinal vasculature. This blood-brain barrier leakage was accompanied by a regionalized and patchy loss of VSMC, with VSMC gaps predominantly in arterial resistance vessels of larger caliber. The loss of VSMC appeared to be caused by progressive degeneration of VSMC resulting in a gradual loss of VSMC marker expression and a progressive acquisition of an aberrant VSMC phenotype closer to the gaps, followed by enhanced apoptosis and cellular disintegration in the gaps. Arterial VSMC were the only mural cell type that was morphologically affected, despite Notch3 also being expressed in pericytes. Transcriptome analysis of isolated brain microvessels revealed gene expression changes in Notch3(-/-) mice consistent with loss of arterial VSMC and presumably secondary transcriptional changes were observed in endothelial genes, which may explain the compromised vascular integrity.
We demonstrate that Notch3 is important for survival of VSMC, and reveal a critical role for Notch3 and VSMC in blood vessel integrity and blood-brain barrier function in the mammalian vasculature.
血管平滑肌细胞（VSMC）对于收缩、血流分布和血管直径的调节非常重要，但它们对血管完整性和血脑屏障功能的贡献程度还不太清楚。在本报告中，我们探讨了 Notch3（-/-）小鼠中 VSMC 缺失对中枢神经系统血管完整性的影响。
Notch3（-/-）小鼠表现出血脑屏障的局灶性破坏，表现为示踪剂外渗伴有视网膜血管中的纤维蛋白沉积。这种血脑屏障渗漏伴随着区域性和斑片状的 VSMC 缺失，VSMC 间隙主要位于较大口径的动脉阻力血管中。VSMC 的缺失似乎是由 VSMC 的进行性退化引起的，导致 VSMC 标志物表达逐渐丧失，并逐渐获得更接近间隙的异常 VSMC 表型，随后在间隙中出现增强的细胞凋亡和细胞崩解。尽管 Notch3 也在周细胞中表达，但动脉 VSMC 是唯一受到形态影响的壁细胞类型。分离的脑微血管的转录组分析显示 Notch3（-/-）小鼠存在与动脉 VSMC 缺失一致的基因表达变化，内皮基因也观察到推测的继发转录变化，这可能解释了血管完整性受损。
我们证明 Notch3 对 VSMC 的存活很重要，并揭示了 Notch3 和 VSMC 在哺乳动物血管中的血管完整性和血脑屏障功能中的关键作用。
