title: Angiogenesis induced by prenatal ischemia predisposes to periventricular hemorrhage during postnatal mechanical ventilation.
abstract: BACKGROUND
  Three risk factors are associated with hemorrhagic forms of encephalopathy of prematurity (EP): (i) prematurity, (ii) in utero ischemia (IUI) or perinatal ischemia, and (iii) mechanical ventilation. We hypothesized that IUI would induce an angiogenic response marked by activation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), the latter degrading vascular basement membrane and increasing vulnerability to raised intravenous pressure during positive pressure mechanical ventilation.
  
  
  METHODS
  We studied a rat model of hemorrhagic-EP characterized by periventricular hemorrhages in which a 20-min episode of IUI is induced at E19, pups are born naturally at E21-22, and on P0, are subjected to a 20-min episode of positive pressure mechanical ventilation. Tissues were studied by H&E staining, immunolabeling, immunoblot, and zymography.
  
  
  RESULTS
  Mechanical ventilation of rat pups 2-3 d after 20-min IUI caused widespread hemorrhages in periventricular tissues. IUI resulted in upregulation of VEGF and MMP-9. Zymography confirmed significantly elevated gelatinase activity. MMP-9 activation was accompanied by severe loss of MMP-9 substrates, collagen IV and laminin, in microvessels in periventricular areas.
  
  
  CONCLUSIONS
  Our findings are consistent with the hypothesis that positive pressure mechanical ventilation of the newborn in the context of recent prenatal ischemia/hypoxia can predispose to periventricular hemorrhages.
authors: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Cigdem
authors: C
authors: Tosun
authors: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Caron
authors: C
authors: Hong
authors: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Brianna
authors: B
authors: Carusillo
authors: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Svetlana
authors: S
authors: Ivanova
authors: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: Volodymyr
authors: V
authors: Gerzanich
authors: 1] Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA [2] Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA [3] Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors: J Marc
authors: JM
authors: Simard
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D024141:Collagen Type IV / Q000737:chemistry; D004195:Disease Models, Animal; D004573:Electrolytes; D005260:Female; D006470:Hemorrhage / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D020300:Intracranial Hemorrhages; D007511:Ischemia / Q000473:pathology*; D007797:Laminin / Q000737:chemistry; D018811:Maternal Exposure; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011247:Pregnancy; D011270:Pregnancy, Animal; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial; D012307:Risk Factors; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D004573:Electrolytes; D007797:Laminin; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat