Imatinib attenuates cerebrovascular injury and phenotypic transformation after intracerebral hemorrhage in rats

William J. Pearce, Coleen Doan, Desirelys Carreon, Dahlim Kim, Lara M. Durrant, Anatol Manaenko, Lauren McCoy, Andre Obenaus, John H. Zhang, Jiping Tang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)R1093-R1104
JournalAmerican journal of physiology. Regulatory, integrative and comparative physiology
Volume311
Issue number6
DOIs
StatePublished - Dec 2016

ASJC Scopus Subject Areas

  • General Medicine

Keywords

  • Cerebral arteries
  • Gleevec
  • Myosin
  • Platelet-derived growth factor
  • STI-571
  • Cerebrovascular Disorders/physiopathology
  • Rats
  • Male
  • Treatment Outcome
  • Rats, Sprague-Dawley
  • Dose-Response Relationship, Drug
  • Phenotype
  • Animals
  • Cerebrovascular Circulation/drug effects
  • Cerebral Hemorrhage/drug therapy
  • Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors
  • Imatinib Mesylate/administration & dosage
  • Cerebral Arteries/drug effects

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