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Regulates Blood-Brain Barrier Permeability via Reactivation of the Hypoxia-Angiogenesis Program1
,¶,¶,
* Corinne Goldsmith Dickinson Center for Multiple Sclerosis,
Department of Neurology, and
Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029; and
Department of Pathology (Neuropathology) and
¶ Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461
Loss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1
, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1 induced the expression of genes favoring vessel plasticity, including HIF-1
and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1 and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1 in the brain induced astrocytic expression of HIF-1, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1-induced HIF-1 in its regulation. These results suggest that IL-1 contributes to BBB permeability in MS via reactivation of the HIF–VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by U.S. Public Health Service Grants NS46620 (to G.R.J.), NS40137 (to C.F.B.), NS11920 (to C.F.B. and C.S.R.), MH55477 (to S.C.L.), National Multiple Sclerosis Society Fellowship FG-1739 (to Y.Z.), the Jayne and Harvey Beker Foundation (to G.R.J.), and Einstein CFAR P30 AI051519 (to S.C.L.). The Mount Sinai School of Medicine/Microscopy Shared Resource Facility is supported, in part, with funding from National Institutes of Health/National Cancer Institute Shared Resources Grant R24 CA095823.
2 Address correspondence and reprint requests to Dr. Gareth John, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029. E-mail address: gareth.john{at}mssm.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; BBB, blood-brain barrier; EAE, experimental autoimmune encephalomyelitis; HBMVEC, human brain microvessel endothelial cells; HIF-1, hypoxia-inducible factor-1; NRP, neuropilin; VEGF, vascular endothelial growth factor; siRNA, small interfering RNA;RT, room temperature; Q-PCR, quantitative real-time PCR; DAPI, 4',6'-diamidino-2-phenylindole.
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