当前位置: X-MOL 学术Dev. Cell › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling
Developmental Cell ( IF 10.7 ) Pub Date : 2022-05-18 , DOI: 10.1016/j.devcel.2022.04.019
Koji Ando 1 , Lei Tong 2 , Di Peng 3 , Elisa Vázquez-Liébanas 3 , Hirohisa Chiyoda 4 , Liqun He 3 , Jianping Liu 5 , Koichi Kawakami 6 , Naoki Mochizuki 7 , Shigetomo Fukuhara 8 , Jaime Grutzendler 2 , Christer Betsholtz 9
Affiliation  

Loss- or gain-of-function mutations in ATP-sensitive potassium channel (K-ATP)-encoding genes, KCNJ8 and ABCC9, cause human central nervous system disorders with unknown pathogenesis. Here, using mice, zebrafish, and cell culture models, we investigated cellular and molecular causes of brain dysfunctions derived from altered K-ATP channel function. We show that genetic/chemical inhibition or activation of KCNJ8/ABCC9-containing K-ATP channel function leads to brain-selective suppression or promotion of arterial/arteriolar vascular smooth muscle cell (VSMC) differentiation, respectively. We further show that brain VSMCs develop from KCNJ8/ABCC9-containing K-ATP channel-expressing mural cell progenitor and that K-ATP channel cell autonomously regulates VSMC differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels. Consistent with defective VSMC development, Kcnj8 knockout mice showed deficiency in vasoconstrictive capacity and neuronal-evoked vasodilation leading to local hyperemia. Our results demonstrate a role for KCNJ8/ABCC9-containing K-ATP channels in the differentiation of brain VSMC, which in turn is necessary for fine-tuning of cerebral blood flow.



中文翻译:

含有 KCNJ8/ABCC9 的 K-ATP 通道调节脑血管平滑肌发育和神经血管耦合

ATP 敏感钾通道 (K-ATP) 编码基因KCNJ8ABCC9的功能丧失或功能获得突变,导致人类中枢神经系统紊乱,发病机制不明。在这里,我们使用小鼠、斑马鱼和细胞培养模型,研究了源自 K-ATP 通道功能改变的脑功能障碍的细胞和分子原因。我们表明,对含有 KCNJ8/ABCC9 的 K-ATP 通道功能的遗传/化学抑制或激活分别导致脑选择性抑制或促进动脉/小动脉血管平滑肌细胞 (VSMC) 分化。我们进一步表明,脑 VSMCs 是从含有 KCNJ8/ABCC9 的表达 K-ATP 通道的壁细胞祖细胞发展而来的,并且 K-ATP 通道细胞通过电压依赖性钙通道调节细胞内 Ca 2+振荡来自主调节 VSMC 分化。与有缺陷的 VSMC 开发一致,Kcnj8基因敲除小鼠表现出血管收缩能力不足和神经元诱发的血管舒张导致局部充血。我们的结果证明了含有 KCNJ8/ABCC9 的 K-ATP 通道在脑 VSMC 分化中的作用,这反过来又是微调脑血流所必需的。

更新日期:2022-05-18
down
wechat
bug