title: Astrocyte-derived CO is a diffusible messenger that mediates glutamate-induced cerebral arteriolar dilation by activating smooth muscle Cell KCa channels.
abstract: Astrocyte signals can modulate arteriolar tone, contributing to regulation of cerebral blood flow, but specific intercellular communication mechanisms are unclear. Here we used isolated cerebral arteriole myocytes, astrocytes, and brain slices to investigate whether carbon monoxide (CO) generated by the enzyme heme oxygenase (HO) acts as an astrocyte-to-myocyte gasotransmitter in the brain. Glutamate stimulated CO production by astrocytes with intact HO-2, but not those genetically deficient in HO-2. Glutamate activated transient K(Ca) currents and single K(Ca) channels in myocytes that were in contact with astrocytes, but did not affect K(Ca) channel activity in myocytes that were alone. Pretreatment of astrocytes with chromium mesoporphyrin (CrMP), a HO inhibitor, or genetic ablation of HO-2 prevented glutamate-induced activation of myocyte transient K(Ca) currents and K(Ca) channels. Glutamate decreased arteriole myocyte intracellular Ca2+ concentration and dilated brain slice arterioles and this decrease and dilation were blocked by CrMP. Brain slice arteriole dilation to glutamate was also blocked by L-2-alpha aminoadipic acid, a selective astrocyte toxin, and paxilline, a K(Ca) channel blocker. These data indicate that an astrocytic signal, notably HO-2-derived CO, is used by glutamate to stimulate arteriole myocyte K(Ca) channels and dilate cerebral arterioles. Our study explains the astrocyte and HO dependence of glutamatergic functional hyperemia observed in the newborn cerebrovascular circulation in vivo.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, USA.
authors.forename: Anlong
authors.initials: A
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Xi
authors.forename: Edward S
authors.initials: ES
authors.lastname: Umstot
authors.forename: Lars
authors.initials: L
authors.lastname: Bellner
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
authors.forename: Charles W
authors.initials: CW
authors.lastname: Leffler
mesh_terms: D001160:Arterioles / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology; D002248:Carbon Monoxide / Q000378:metabolism / Q000502:physiology*; D002560:Cerebrovascular Circulation; D005971:Glutamates / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000737:chemistry / Q000378:metabolism*; D019899:Paracrine Communication; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D015290:Second Messenger Systems; D014664:Vasodilation
chemical_list: D005971:Glutamates; D024681:Potassium Channels, Calcium-Activated; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2