Age-dependent neonatal intracerebral hemorrhage in plasminogen activator inhibitor 1 knockout mice.
Intracerebral-intraventricular hemorrhages (ICH/IVH) in very preterm neonates are responsible for high mortality and subsequent disabilities. In humans, tissue plasminogen activator (t-PA) initiates fibrinolysis and activates endoluminal-endothelial receptors; dysfunction of the t-PA inhibitor (PAI-1) results in recurrent hemorrhages. We used PAI-1 knockout (PAI-1) mice to examine the role of t-PA in age-dependent intracranial hemorrhages as a possible model of preterm ICH/IVH. Intracortical injection of 2 μL of phosphate-buffered saline produced a small traumatic injury and a high rate of hemorrhage in PAI-1 pups at postnatal day 3 (P3) or P5, whereas it had no effect in wild-type neonates. This resulted in white matter and cortical lesions, ventricle enlargement, hyperlocomotion, and altered cortical levels of serotonin and dopamine in the adult PAI mice. N-methyl-D-aspartate receptor blockers, plasmin- and matrix metalloproteinases inhibitors reduced hemorrhage and tissue lesions. In contrast to P3 to P5, no significant hemorrhages were induced in P10 PAI-1 pups and there were no behavioral or neurochemical alterations in adulthood. These data suggest that microvascular immaturity up to P5 in mice is a determinant factor required for t-PA-dependent vascular rupture. Neonatal PAI-1 mice could be a useful ICH/IVH model for studying the ontogenic window of vascular immaturity and vascular protection against later neurodisabilities.
From the Laboratory of Microvascular Endothelium and Neonate Brain Lesions (PL, PLO, ND, BJG, CB-L, IL-N, SM), INSERM-Région Haute-Normandie Team ERI-28, Institute for Research and Innovation in Biomedicine and Laboratory of Psychology and Neuroscience of Cognition and Affects (VR), PSY-NCA, University of Rouen, Rouen; Department of Biochemistry (CB-L), IBC and Department of Neonatal Pediatrics and Intensive Care (SM), Rouen University Hospital, Rouen, France; and Laboratory of Angiogenesis and Neurovascular Link (PC), Vesalius Research Center, VIB and Laboratory of Angiogenesis and Neurovascular Link (PC), Department of Oncology, KU Leuven, Belgium.
Philippe
P
Leroux
Priscilla L
PL
Omouendze
Vincent
V
Roy
Nathalie
N
Dourmap
Bruno J
BJ
Gonzalez
Carole
C
Brasse-Lagnel
Peter
P
Carmeliet
Isabelle
I
Leroux-Nicollet
Stéphane
S
Marret
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D015119:Aminocaproic Acid / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D007611:Aprotinin / Q000008:administration & dosage; D002543:Cerebral Hemorrhage / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010641:Phenotype; D058258:Serpin E2 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology
D058258:Serpin E2; C511869:Serpine2 protein, mouse; D007611:Aprotinin; D015119:Aminocaproic Acid