TY - JOUR
T1 - Imatinib attenuates cerebrovascular injury and phenotypic transformation after intracerebral hemorrhage in rats
AU - Pearce, William J.
AU - Doan, Coleen
AU - Carreon, Desirelys
AU - Kim, Dahlim
AU - Durrant, Lara M.
AU - Manaenko, Anatol
AU - McCoy, Lauren
AU - Obenaus, Andre
AU - Zhang, John H.
AU - Tang, Jiping
N1 - Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/12
Y1 - 2016/12
N2 - 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.
AB - 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.
KW - Cerebral arteries
KW - Gleevec
KW - Myosin
KW - Platelet-derived growth factor
KW - STI-571
KW - Cerebrovascular Disorders/physiopathology
KW - Rats
KW - Male
KW - Treatment Outcome
KW - Rats, Sprague-Dawley
KW - Dose-Response Relationship, Drug
KW - Phenotype
KW - Animals
KW - Cerebrovascular Circulation/drug effects
KW - Cerebral Hemorrhage/drug therapy
KW - Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors
KW - Imatinib Mesylate/administration & dosage
KW - Cerebral Arteries/drug effects
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UR - http://www.scopus.com/inward/citedby.url?scp=85002731425&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/458908ad-bead-39d5-8e95-2ee46fc1312e/
U2 - 10.1152/ajpregu.00240.2016
DO - 10.1152/ajpregu.00240.2016
M3 - Article
C2 - 27707720
SN - 0363-6119
VL - 311
SP - R1093-R1104
JO - American journal of physiology. Regulatory, integrative and comparative physiology
JF - American journal of physiology. Regulatory, integrative and comparative physiology
IS - 6
ER -