title: Arterial Smooth Muscle Mitochondria Amplify Hydrogen Peroxide Microdomains Functionally Coupled to L-Type Calcium Channels.
abstract: BACKGROUND
  Mitochondria are key integrators of convergent intracellular signaling pathways. Two important second messengers modulated by mitochondria are calcium and reactive oxygen species. To date, coherent mechanisms describing mitochondrial integration of calcium and oxidative signaling in arterial smooth muscle are incomplete.
  
  
  OBJECTIVE
  To address and add clarity to this issue, we tested the hypothesis that mitochondria regulate subplasmalemmal calcium and hydrogen peroxide microdomain signaling in cerebral arterial smooth muscle.
  
  
  RESULTS
  Using an image-based approach, we investigated the impact of mitochondrial regulation of L-type calcium channels on subcellular calcium and reactive oxygen species signaling microdomains in isolated arterial smooth muscle cells. Our single-cell observations were then related experimentally to intact arterial segments and to living animals. We found that subplasmalemmal mitochondrial amplification of hydrogen peroxide microdomain signaling stimulates L-type calcium channels, and that this mechanism strongly impacts the functional capacity of the vasoconstrictor angiotensin II. Importantly, we also found that disrupting this mitochondrial amplification mechanism in vivo normalized arterial function and attenuated the hypertensive response to systemic endothelial dysfunction.
  
  
  CONCLUSIONS
  From these observations, we conclude that mitochondrial amplification of subplasmalemmal calcium and hydrogen peroxide microdomain signaling is a fundamental mechanism regulating arterial smooth muscle function. As the principle components involved are fairly ubiquitous and positioning of mitochondria near the plasma membrane is not restricted to arterial smooth muscle, this mechanism could occur in many cell types and contribute to pathological elevations of intracellular calcium and increased oxidative stress associated with many diseases.
authors.affiliation: From the Department of Biomedical Sciences, Colorado State University, Fort Collins (N.L.C., A.M.F., G.C.A.); and Department of Pharmacology, University of California, Davis (M.N.-C., M.F.N.).
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Chaplin
authors.affiliation: From the Department of Biomedical Sciences, Colorado State University, Fort Collins (N.L.C., A.M.F., G.C.A.); and Department of Pharmacology, University of California, Davis (M.N.-C., M.F.N.).
authors.forename: Madeline
authors.initials: M
authors.lastname: Nieves-Cintrón
authors.affiliation: From the Department of Biomedical Sciences, Colorado State University, Fort Collins (N.L.C., A.M.F., G.C.A.); and Department of Pharmacology, University of California, Davis (M.N.-C., M.F.N.).
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Fresquez
authors.affiliation: From the Department of Biomedical Sciences, Colorado State University, Fort Collins (N.L.C., A.M.F., G.C.A.); and Department of Pharmacology, University of California, Davis (M.N.-C., M.F.N.).
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Navedo
authors.affiliation: From the Department of Biomedical Sciences, Colorado State University, Fort Collins (N.L.C., A.M.F., G.C.A.); and Department of Pharmacology, University of California, Davis (M.N.-C., M.F.N.). Gregory.Amberg@colostate.edu.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Amberg
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002536:Cerebral Arteries / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide
keywords: calcium channels; hypertension myocytes, smooth muscle; oxidative stress; reactive oxygen species