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Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function.

ABSTRACT: Cirrhosis is associated with prominent changes in sinusoidal structure and function. Although the resident pericyte in liver, the hepatic stellate cell (HSC), is well characterized in the process of fibrogenesis, signaling pathways that regulate HSC vascular function are less developed. Because pericyte populations outside the liver are increasingly being recognized as a key cell type for angiogenesis and changes in vascular structure, in this study, we explore new HSC-signaling pathways that regulate sinusoidal structure and function.Real-time video microscopy and quantitative software analysis of vascular tube formation were used to measure HSC angiogenesis in vitro. Platelet-derived growth factor (PDGF) and ephrin-signaling pathways were modulated using molecular and pharmacologic techniques. Complementary whole animal studies were performed to correlate in vitro findings with pericyte functions in vivo.We show that PDGF promotes a phenotype of HSC evidenced by enhanced HSC-driven vascular tube formation in vitro and enhanced HSC coverage of sinusoids in vivo. This angiogenic phenotype modulates specific pericyte vascular functions including permeability and pressure regulation. Furthermore, we identify a key role for ephrin-B2 as a downstream effector of PDGF signaling.These studies elucidate novel HSC-signaling pathways that regulate microvascular structure and function in liver.

SUBMITTER: Semela D

PROVIDER: S-EPMC2639748 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function.

Semela David D Das Amitava A Langer Daniel D Kang Ningling N Leof Edward E Shah Vijay V

Gastroenterology 20080416 2

<h4>Background & aims</h4>Cirrhosis is associated with prominent changes in sinusoidal structure and function. Although the resident pericyte in liver, the hepatic stellate cell (HSC), is well characterized in the process of fibrogenesis, signaling pathways that regulate HSC vascular function are less developed. Because pericyte populations outside the liver are increasingly being recognized as a key cell type for angiogenesis and changes in vascular structure, in this study, we explore new HSC- ...[more]

PMID: 18570897

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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-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function.

Publications

Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function.

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