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Platelet factor 4 mediates vascular smooth muscle cell injury responses.

ABSTRACT: Activated platelets release many inflammatory molecules with important roles in accelerating vascular inflammation. Much is known about platelet and platelet-derived mediator interactions with endothelial cells and leukocytes, but few studies have examined the effects of platelets on components of the vascular wall. Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to injury including the production of inflammatory molecules, cell proliferation, cell migration, and a decline in the expression of differentiation markers. In this study, we demonstrate that the platelet-derived chemokine platelet factor 4 (PF4/CXCL4) stimulates VSMC injury responses both in vitro and in vivo in a mouse carotid ligation model. PF4 drives a VSMC inflammatory phenotype including a decline in differentiation markers, increased cytokine production, and cell proliferation. We also demonstrate that PF4 effects are mediated, in part, through increased expression of the transcription factor Krüppel-like factor 4. Our data indicate an important mechanistic role for platelets and PF4 in VSMC injury responses both in vitro and in vivo.

SUBMITTER: Shi G

PROVIDER: S-EPMC3663434 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Platelet factor 4 mediates vascular smooth muscle cell injury responses.

Shi Guanfang G Field David J DJ Long Xiaochun X Mickelsen Deanne D Ko Kyung-ae KA Ture Sara S Korshunov Vyacheslav A VA Miano Joseph M JM Morrell Craig N CN

Blood 20130408 21

Activated platelets release many inflammatory molecules with important roles in accelerating vascular inflammation. Much is known about platelet and platelet-derived mediator interactions with endothelial cells and leukocytes, but few studies have examined the effects of platelets on components of the vascular wall. Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to injury including the production of inflammatory molecules, cell proliferation, cell migration, and a de ...[more]

PMID: 23568488

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Project description:Platelet-derived growth factor-BB activates platelet-derived growth factor receptor-? and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-muscle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such as intercellular adhesion molecule-1, which can amplify neutrophil infiltration into the brain. In the present study, we investigated the role of platelet-derived growth factor-BB/platelet-derived growth factor receptor-? following intracerebral hemorrhage-induced brain injury in mice, with emphasis on its ability to promote vascular smooth muscle cell phenotypic transformation followed by increased intercellular adhesion molecule-1 expression and elevated neutrophil infiltration in the vicinity of the hematoma. We also determined the extent to which plasmin from the hematoma influences the platelet-derived growth factor-BB/platelet-derived growth factor receptor-? system subsequent to intracerebral hemorrhage.Controlled in vivo laboratory study.Animal research laboratory.One hundred and fifty six eight-week-old male CD1 mice.Brain injury was induced by autologous arterial blood or plasmin injection into mouse brains. Small interfering RNA targeting platelet-derived growth factor receptor-? was administered 24 hours before intracerebral hemorrhage. A platelet-derived growth factor receptor antagonist, Gleevec, was administered following intracerebral hemorrhage. A mitogen-activated protein kinase-activated protein kinase 2 inhibitor (KKKALNRQLGVAA) was delivered with platelet-derived growth factor-BB in naïve animals. Platelet-derived growth factor-BB was injected with a plasmin inhibitor (?-aminocaproic acid) in intracerebral hemorrhage mice. Plasmin-injected mice were given platelet-derived growth factor receptor-? small interfering RNA 24 hours before the operation. Neurological deficits, brain edema, western blots, and immunofluorescence were evaluated.Platelet-derived growth factor receptor-? small interfering RNA attenuated SMemb and intercellular adhesion molecule-1 expression and neutrophil infiltration at 24 hours post injury and reduced neurological deficits and brain edema at 24 and 72 hours following intracerebral hemorrhage. The platelet-derived growth factor receptor antagonist, Gleevec, reduced SMemb and intercellular adhesion molecule-1 expression. Platelet-derived growth factor receptor-? activation led to increased expression of intercellular adhesion molecule-1 and was reversed by KKKALNRQLGVAA in naïve mice. Plasmin inhibition suppressed platelet-derived growth factor receptor-? activation and neutrophil infiltration, whereas exogenous platelet-derived growth factor-BB increased platelet-derived growth factor receptor-? activation, regardless of plasmin inhibition. Platelet-derived growth factor receptor-? small interfering RNA decreased the expression of intercellular adhesion molecule-1 by plasmin injection.The platelet-derived growth factor-BB/platelet-derived growth factor receptor-? system contributes to neuroinflammation through vascular smooth muscle cell phenotypic transformation near the hematoma via the p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 pathway following intracerebral hemorrhage. Plasmin is hypothesized to be upstream of the proposed neuroinflammatory system. The therapeutic intervention targeting the platelet-derived growth factor-BB/platelet-derived growth factor receptor-? is a novel strategy to prevent plasmin-induced brain injury following intracerebral hemorrhage.

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Platelet factor 4 mediates vascular smooth muscle cell injury responses.

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Platelet factor 4 mediates vascular smooth muscle cell injury responses.

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