title: Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn.
abstract: BACKGROUND
  Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood.
  
  
  OBJECTIVE
  To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms.
  
  
  RESULTS
  PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC) were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB.
  
  
  CONCLUSIONS
  Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN.
authors: Department of Pediatrics, University of California Davis Medical Center Sacramento, CA, USA.
authors: Stephen
authors: S
authors: Wedgwood
authors: Department of Pediatrics, State University of New York at Buffalo Buffalo, NY, USA.
authors: Satyan
authors: S
authors: Lakshminrusimha
authors: Department of Pediatrics, Northwestern University Chicago, IL, USA.
authors: Paul T
authors: PT
authors: Schumacker
authors: Department of Pediatrics, University of California Davis Medical Center Sacramento, CA, USA.
authors: Robin H
authors: RH
authors: Steinhorn
keywords: HIF-1α; hypoxia; pulmonary hypertension; reactive oxygen species; vascular stress