title: Mechanotransduction drives post ischemic revascularization through K(ATP) channel closure and production of reactive oxygen species.
abstract: OBJECTIVE
  We reported earlier that ischemia results in the generation of reactive oxygen species (ROS) via the closure of a K(ATP) channel which causes membrane depolarization and NADPH oxidase 2 (NOX2) activation. This study was undertaken to understand the role of ischemia-mediated ROS in signaling.
  
  
  RESULTS
  Angiogenic potential of pulmonary microvascular endothelial cells (PMVEC) was studied in vitro and in the hind limb in vivo. Flow adapted PMVEC injected into a Matrigel matrix showed significantly higher tube formation than cells grown under static conditions or cells from mice with knockout of K(ATP) channels or the NOX2. Blocking of hypoxia inducible factor-1 alpha (HIF-1α) accumulation completely abrogated the tube formation in wild-type (WT) PMVEC. With ischemia in vivo (femoral artery ligation), revascularization was high in WT mice and was significantly decreased in mice with knockout of K(ATP) channel and in mice orally fed with a K(ATP) channel agonist. In transgenic mice with endothelial-specific NOX2 expression, the revascularization observed was intermediate between that of WT and knockout of K(ATP) channel or NOX2. Increased HIF-1α activation and vascular endothelial growth factor (VEGF) expression was observed in ischemic tissue of WT mice but not in K(ATP) channel and NOX2 null mice. Revascularization could be partially rescued in K(ATP) channel null mice by delivering VEGF into the hind limb.
  
  
  METHODS
  This is the first report of a mechanosensitive ion channel (K(ATP) channel) initiating endothelial signaling that drives revascularization.
  
  
  CONCLUSIONS
  The K(ATP) channel responds to the stop of flow and activates signals for revascularization to restore the impeded blood flow.
authors.affiliation: 1 Institute for Environmental Medicine, University of Pennsylvania , Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Browning
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Nankang
authors.initials: N
authors.lastname: Hong
authors.forename: Kevin
authors.initials: K
authors.lastname: Yu
authors.forename: Donald G
authors.initials: DG
authors.lastname: Buerk
authors.forename: Kristine
authors.initials: K
authors.lastname: DeBolt
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonder
authors.forename: Elena M
authors.initials: EM
authors.lastname: Sorokina
authors.forename: Puja
authors.initials: P
authors.lastname: Patel
authors.forename: Diva D
authors.initials: DD
authors.lastname: De Leon
authors.forename: Sheldon I
authors.initials: SI
authors.lastname: Feinstein
authors.forename: Aron B
authors.initials: AB
authors.lastname: Fisher
authors.forename: Shampa
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D054086:KATP Channels; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D051547:Heme Oxygenase-1