title: Imatinib attenuates cerebrovascular injury and phenotypic transformation after intracerebral hemorrhage in rats.
abstract: This study explored the hypothesis that intracerebral hemorrhage (ICH) promotes release of diffusible factors that can significantly influence the structure and function of cerebral arteries remote from the site of injury, through action on platelet-derived growth factor (PDGF) receptors. Four groups of adult male Sprague-Dawley rats were studied (n = 8 each): 1) sham; 2) sham + 60 mg/kg ip imatinib; 3) ICH (collagenase method); and 4) ICH + 60 mg/kg ip imatinib given 60 min after injury. At 24 h after injury, sham artery passive diameters (+3 mM EGTA) averaged 244 ± 7 µm (at 60 mmHg). ICH significantly increased passive diameters up to 6.4% and decreased compliance up to 42.5%. For both pressure- and potassium-induced contractions, ICH decreased calcium mobilization up to 26.2% and increased myofilament calcium sensitivity up to 48.4%. ICH reduced confocal colocalization of smooth muscle α-actin (αActin) with nonmuscle myosin heavy chain (MHC) and increased its colocalization with smooth muscle MHC, suggesting that ICH promoted contractile differentiation. ICH also enhanced colocalization of myosin light chain kinase (MLCK) with both αActin and regulatory 20-kDa myosin light chain. All effects of ICH on passive diameter, compliance, contractility, and contractile protein colocalization were significantly reduced or absent in arteries from animals treated with imatinib. These findings support the hypothesis that ICH promotes release into the cerebrospinal fluid of vasoactive factors that can diffuse to and promote activation of cerebrovascular PDGF receptors, thereby altering the structure, contractile protein organization, contractility, and smooth muscle phenotype of cerebral arteries remote from the site of hemorrhage.
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California; wpearce@llu.edu.|Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.|Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Coleen
authors.initials: C
authors.lastname: Doan
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.|Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Desirelys
authors.initials: D
authors.lastname: Carreon
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.|Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Dahlim
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.|Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Lara M
authors.initials: LM
authors.lastname: Durrant
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California; and.
authors.forename: Lauren
authors.initials: L
authors.lastname: McCoy
authors.affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California; and.
authors.forename: Andre
authors.initials: A
authors.lastname: Obenaus
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.|Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, California.|Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Department of Pharmacology, Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology*; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000503:physiopathology* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D000068877:Imatinib Mesylate / Q000008:administration & dosage*; D008297:Male; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor
keywords: Gleevec; STI-571; cerebral arteries; myosin; platelet-derived growth factor