Dataset Information

Linking Notch signaling to ischemic stroke.

ABSTRACT: Vascular smooth muscle cells (SMCs) have been implicated in the pathophysiology of stroke, the third most common cause of death and the leading cause of long-term neurological disability in the world. However, there is little insight into the underlying cellular pathways that link SMC function to brain ischemia susceptibility. Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.

SUBMITTER: Arboleda-Velasquez JF

PROVIDER: S-EPMC2290794 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Linking Notch signaling to ischemic stroke.

Arboleda-Velasquez Joseph F JF Zhou Zhipeng Z Shin Hwa Kyoung HK Louvi Angeliki A Kim Hyung-Hwan HH Savitz Sean I SI Liao James K JK Salomone Salvatore S Ayata Cenk C Moskowitz Michael A MA Artavanis-Tsakonas Spyros S

Proceedings of the National Academy of Sciences of the United States of America 20080317 12

Vascular smooth muscle cells (SMCs) have been implicated in the pathophysiology of stroke, the third most common cause of death and the leading cause of long-term neurological disability in the world. However, there is little insight into the underlying cellular pathways that link SMC function to brain ischemia susceptibility. Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibil ...[more]

PMID: 18347334

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Project description:BackgroundIschemic stroke provokes a neuroinflammatory response and simultaneously promotes release of epinephrine and norepinephrine by the sympathetic nervous system. This increased sympathetic outflow can act on β2-adrenergic receptors expressed by immune cells such as brain-resident microglia and monocyte-derived macrophages (MDMs), but the effect on post-stroke neuroinflammation is unknown. Thus, we investigated how changes in β2-adrenergic signaling after stroke onset influence the microglia/MDM stroke response, and the specific importance of microglia/MDM β2-adrenergic receptors to post-stroke neuroinflammation.MethodsTo investigate the effects of β2-adrenergic receptor manipulation on post-stroke neuroinflammation, we administered the β2-adrenergic receptor agonist clenbuterol to mice 3 h after the onset of photothrombotic stroke. We immunostained to quantify microglia/MDM numbers and proliferation and to assess morphology and activation 3 days later. We assessed stroke outcomes by measuring infarct volume and functional motor recovery and analyzed gene expression levels of neuroinflammatory molecules. Finally, we evaluated changes in cytokine expression and microglia/MDM response in brains of mice with selective knockout of the β2-adrenergic receptor from microglia and monocyte-lineage cells.ResultsWe report that clenbuterol treatment after stroke onset causes enlarged microglia/MDMs and impairs their proliferation, resulting in reduced numbers of these cells in the peri-infarct cortex by 1.7-fold at 3 days after stroke. These changes in microglia/MDMs were associated with increased infarct volume in clenbuterol-treated animals. In mice that had the β2-adrenergic receptor specifically knocked out of microglia/MDMs, there was no change in morphology or numbers of these cells after stroke. However, knockdown of β2-adrenergic receptors in microglia and MDMs resulted in increased expression of TNFα and IL-10 in peri-infarct tissue, while stimulation of β2-adrenergic receptors with clenbuterol had the opposite effect, suppressing TNFα and IL-10 expression.ConclusionsWe identified β2-adrenergic receptor signaling as an important regulator of the neuroimmune response after ischemic stroke. Increased β2-adrenergic signaling after stroke onset generally suppressed the microglia/MDM response, reducing upregulation of both pro- and anti-inflammatory cytokines, and increasing stroke size. In contrast, diminished β2-adrenergic signaling in microglia/MDMs augmented both pro- and anti-inflammatory cytokine expression after stroke. The β2-adrenergic receptor may therefore present a therapeutic target for improving the post-stroke neuroinflammatory and repair process.

Dataset Information

Linking Notch signaling to ischemic stroke.

Publications

Linking Notch signaling to ischemic stroke.

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