PUBLICATION

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

Authors
Ando, K., Tong, L., Peng, D., Vázquez-Liébanas, E., Chiyoda, H., He, L., Liu, J., Kawakami, K., Mochizuki, N., Fukuhara, S., Grutzendler, J., Betsholtz, C.
ID
ZDB-PUB-220520-10
Date
2022
Source
Developmental Cell   57(11): 1383-1399.e7 (Journal)
Registered Authors
Ando, Koji, Betsholtz, Christer, Fukuhara, Shigetomo, Kawakami, Koichi, Mochizuki, Naoki
Keywords
ABCC9, KCNJ8, cerebral blood flow, functional hyperaemia, neuro-vascular coupling, pericytes, vascular smooth muscle cells
MeSH Terms
  • Adenosine Triphosphate
  • Animals
  • Brain/metabolism
  • KATP Channels/genetics
  • KATP Channels/metabolism*
  • Mice
  • Muscle, Smooth, Vascular*/metabolism
  • Myocytes, Smooth Muscle/metabolism
  • Neurovascular Coupling*
  • Sulfonylurea Receptors/chemistry
  • Sulfonylurea Receptors/genetics
  • Sulfonylurea Receptors/metabolism*
  • Zebrafish/metabolism
PubMed
35588738 Full text @ Dev. Cell
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes