The Role of Matrix Metalloproteinases in Neurovascular Injury
Cell–matrix homeostasis is vital in the CNS. In a large number of CNS disorders, abnormal activation of extracellular proteases may disrupt neuronal function by degrading neurovascular matrix integrity. This chapter surveys the role of a key family of ext
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The Role of Matrix Metalloproteinases in Neurovascular Injury Ji Hae Seo, Shuzhen Guo, Josephine Lok, Deepti Navaratna, Changhong Xing, and Eng H. Lo
Abstract Cell–matrix homeostasis is vital in the CNS. In a large number of CNS disorders, abnormal activation of extracellular proteases may disrupt neuronal function by degrading neurovascular matrix integrity. This chapter surveys the role of a key family of extracellular proteases, the matrix metalloproteinases (MMPs), in stroke and brain injury. Blood–brain barrier (BBB) leakage and brain edema is a critical part of stroke pathophysiology. A large body of data in both experimental models as well as clinical patient populations suggests that MMPs may disrupt BBB permeability and interfere with cell–cell signaling between neuronal, glial, and vascular compartments. Hence, ongoing efforts are underway to validate MMPs as potential therapeutic targets as well as biomarkers in stroke. Because BBB perturbations may also occur in neurodegeneration, MMPs and associated neurovascular mechanisms may also be potential targets in a broader range of CNS disorders. Keywords Matrix metalloproteinase • Edema • Hemorrhage • Blood–brain barrier • Stroke • Trauma
J.H. Seo • S. Guo • J. Lok • D. Navaratna • C. Xing • E.H. Lo (*) Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] N.S. Dhalla and S. Chakraborti (eds.), Role of Proteases in Cellular Dysfunction, Advances in Biochemistry in Health and Disease 8, DOI 10.1007/978-1-4614-9099-9_5, © Springer Science+Business Media New York 2014
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Introduction
The concept of the neurovascular unit emphasizes that central nervous system (CNS) function requires cross talk between all cell types in neuronal, glial, and vascular compartments. In order for these cell–cell signals to operate, intercellular matrix integrity is vital. Hence, any disorders that abnormally activate extracellular proteolysis may disrupt matrix homeostasis, interfere with normal cell–cell and cell–matrix signaling, and further amplify disease pathophysiology. In this regard, enzymes from the family of matrix metalloproteinases (MMPs) have been shown to play significant roles in a wide spectrum of CNS disorders including stroke, brain trauma, and neurodegeneration. This chapter will survey the role of MMPs in mediating neurovascular injury in the context of stroke.
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The Blood–Brain Barrier and Edema
From a clinical standpoint, disruption of neurovascular matrix most clearly manifests as damage to the blood–brain barrier (BBB). The BBB comprises a critical interface between the CNS and the rest of the body. Its primary function is to help regulate the microenvironment of the CNS. To do so, the BBB functions both as a true barrier and a dynamically controlled influx/eff
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