2. Academic Validation
  3. KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling

KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling

  • Dev Cell. 2022 Jun 6;57(11):1383-1399.e7. 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
Affiliations

Affiliations

  • 1 Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85 Uppsala, Sweden; Department of Molecular Pathophysiology, Institute of Advanced Medical Science, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan; Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shinmachi, Suita, Osaka 564-8565, Japan. Electronic address: [email protected].
  • 2 Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
  • 3 Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85 Uppsala, Sweden.
  • 4 Department of Molecular Pathophysiology, Institute of Advanced Medical Science, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan; Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shinmachi, Suita, Osaka 564-8565, Japan.
  • 5 Department of Medicine Huddinge (MedH), Karolinska Institute, Campus Flemingsburg, Neo, Blickagången 16, 141 57 Huddinge, Sweden.
  • 6 Laboratory of Molecular and Developmental Biology, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan; Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
  • 7 Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shinmachi, Suita, Osaka 564-8565, Japan.
  • 8 Department of Molecular Pathophysiology, Institute of Advanced Medical Science, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan.
  • 9 Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, 751 85 Uppsala, Sweden; Department of Medicine Huddinge (MedH), Karolinska Institute, Campus Flemingsburg, Neo, Blickagången 16, 141 57 Huddinge, Sweden. Electronic address: [email protected].
PMID: 35588738 DOI: 10.1016/j.devcel.2022.04.019
Abstract

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.

Keywords

ABCC9; KCNJ8; cerebral blood flow; functional hyperaemia; neuro-vascular coupling; pericytes; vascular smooth muscle cells.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14290A
    99.85%, Potassium Channel Activator