title: Cerebral microvascular damage occurs early after hypoxia-ischemia via nNOS activation in the neonatal brain.
abstract: Microvascular injury early after hypoxic ischemia (HI) may contribute to neonatal brain damage. N-methyl-D-aspartate receptor overstimulation activates neuronal nitric oxide synthases (nNOS). We hypothesized that microvascular damage occurs early post-HI via nNOS activation and contributes to brain injury. Postpartum day-7 rat pups were treated with 7-nitroindazole (7-NI) or aminoguanidine (AG) before or after HI. Electron microscopy was performed to measure neuronal and endothelial cell damage. There were vascular lumen narrowing at 1 hour, pyknotic neurons at 3 hours, and extensive neuronal damage and loss of vessels at 24 hours post HI. Early after reoxygenation, there were neurons with heterochromatic chromatin and endothelial cells with enlarged nuclei occluding the lumen. There was also increased 3-nitrotyrosin in the microvessels and decreased cerebral blood perfusion. 7-NI and AG treatment before hypoxia provided complete and partial neuroprotection, respectively. Early post-reoxygenation, the AG group showed significantly increased microvascular nitrosative stress, microvascular interruptions, swollen nuclei that narrowed the vascular lumen, and decreased cerebral perfusion. The 7-NI group showed significantly decreased microvascular nitrosative stress, patent vascular lumen, and increased cerebral perfusion. Our results indicate that microvascular damage occurs early and progressively post HI. Neuronal nitric oxide synthases activation contributes to microvascular damage and decreased cerebral perfusion early after reoxygenation and worsens brain damage.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan City, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics, Chang Gung Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung City, Taiwan.
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Chang
authors.affiliation: 1] Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan City, Taiwan [2] Department of Pediatrics, National Cheng Kung University Hospital, Tainan City, Taiwan.
authors.forename: Yung-Chieh
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Institute of Cell Biology and Anatomy, National Cheng Kung University Medical College, Tainan City, Taiwan.
authors.forename: Chun-I
authors.initials: CI
authors.lastname: Sze
authors.affiliation: 1] Department of Pediatrics, National Cheng Kung University Hospital, Tainan City, Taiwan [2] Department of Pediatrics, Taipei Medical University, College of Medicine, Taipei, Taiwan.
authors.forename: Chao-Ching
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, National Cheng Kung University Hospital, Tainan City, Taiwan.
authors.forename: Chien-Jung
authors.initials: CJ
authors.lastname: Ho
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002560:Cerebrovascular Circulation / Q000502:physiology*; D042783:Endothelial Cells / Q000201:enzymology / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000201:enzymology / Q000648:ultrastructure; D004789:Enzyme Activation; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000201:enzymology / Q000648:ultrastructure*; D009474:Neurons / Q000201:enzymology / Q000648:ultrastructure; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D052248:Nitric Oxide Synthase Type I; D010100:Oxygen