title: Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice.
abstract: Oxidative stress and matrix metalloproteinases (MMPs) contribute to hemorrhagic transformation after ischemic stroke and brain injury after intracerebral hemorrhage (ICH). The goal of this study was to develop a new model of spontaneous ICH, based on the hypothesis that acute, superimposed on chronic, hypertension produces ICH. We hypothesized that increases in angiotensin II (AngII)-mediated oxidative stress and activation of MMPs are associated with, and may precede, spontaneous ICH during hypertension. In C57BL/6 mice, chronic hypertension was produced with AngII infusion and an inhibitor of nitric oxide synthase. During chronic hypertension, mice with acute hypertension from injections of AngII developed ICH. Oxidative stress and MMP levels increased in the brain even before developing ICH. Active MMPs colocalized with a marker of oxidative stress, especially on cerebral vessels that appeared to lead toward regions with ICH. Incidence of ICH and levels of oxidative stress and MMP-9 were greater in mice with acute hypertension produced by AngII than by norepinephrine. In summary, we have developed an experimental model of ICH during hypertension that may facilitate studies in genetically altered mice. We speculate that acute hypertension, especially when induced by AngII, may be critical in spontaneous ICH during chronic hypertension, possibly through oxidative stress and MMP-9.
authors.affiliation: Department of Internal Medicine, Cardiovascular Center, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Wakisaka
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Miller
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000208:Acute Disease; D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002908:Chronic Disease; D005455:Fluorescent Antibody Technique; D005780:Gelatin; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D007150:Immunohistochemistry; D020300:Intracranial Hemorrhages / Q000209:etiology* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine; D018384:Oxidative Stress / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000473:pathology; D014662:Vasoconstrictor Agents
chemical_list: D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D005780:Gelatin; D020782:Matrix Metalloproteinases; D009638:Norepinephrine