An in depth discussion of the transcription and regulation of MMPs is beyond the scope of the present review we refer readers to some excellent reviews on the control of MMP activity (Ra and Parks, 2007 Clark et al., 2008 Fanjul-Fernández et al., 2010). Indeed, MMPs are normally expressed at very low levels under normal conditions with localized expression induced when remodeling of the ECM is required. MMP is activity is further controlled by the availability and affinity of substrates. However, given that one cysteine residue in the pro-peptide domain coordinates the catalytic site, disruption of this site via S-nitrosylation can also activate MMP-9 (Gu et al., 2002 Manabe et al., 2005 McCarthy et al., 2008). Cleavage of the prop-peptide renders the MMP proteolytically active. Given that uncontrolled expression of MMPs can result in tissue injury and destruction, the catalytic activity of MMPs is regulated at four points, which are: gene expression level, compartmentalization of the MMPs, pro-enzyme activation, and enzyme inactivation (Ra and Parks, 2007). However, action of the MMPs, including MMP-9, have been well documented to play critical roles in tissue repair and remodeling following stroke (Lenglet et al., 2015), particularly in angiogenesis and re-establishment of cerebral blood flow with long-term MMP inhibition shown to markedly reduce neuronal plasticity and impair vascular remodeling (Zhao et al., 2006, 2007).
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The MMPs may have pleiotropic actions on target tissues, with MMPs integrally involved in the normal remodeling of tissue during development and homeostasis but dysregulation of MMPs is implicated in disease states and has repercussions for BBB integrity, tissue injury and cell death (Agrawal et al., 2008). As such, recognized targets of MMP-9 include components of the ECM, tight junction components, growth factors and their precursors, cell surface receptors and cell adhesion molecules (Bajor and Kaczmarek, 2013 Vandooren et al., 2013 Conant et al., 2015). MMPs regulate many aspects of cellular activity with functions ranging from ECM degradation, cell proliferation, adhesion, and migration to release of ECM-sequestered molecules by proteolysis, shedding of cell-surface proteins that transduce signals from the ECM (Cunningham et al., 2005) and activation of pro-inflammatory cytokines (Candelario-Jalil et al., 2009). However, the aim of the present review was to explore the potential relationship between neutrophil-derived MMP-9 and complications such as BBB disruption and HT following stroke to elucidate the cellular source of MMP-9 in ischemic stroke. Although it is generally accepted that MMP-9 is increased following stroke, there is debate as to which cells are responsible, whether it be resident brain cells, cells of the vasculature or circulating immune cells, such as neutrophils. However, the cellular source of this MMP-9 remains controversial. Numerous clinical and experimental studies have confirmed an increase in serum MMP-9 following stroke (Clark et al., 1997 Romanic et al., 1998 Yushchenko et al., 2000 Montaner et al., 2003a Ning et al., 2006).
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Elucidating the mechanisms of such deleterious events is the key to developing targeted, more effective clinical therapies. Cerebral edema and HT of the infarct are significant problems in clinical stroke, which are associated with poor outcome and contribute to the morbidity and mortality of this condition (Hacke et al., 1996 Fiorelli et al., 1999).
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In particular, MMP-9 has been implicated, not only in the pathogenesis of BBB breakdown and subsequent vasogenic edema formation following stroke (Fujimura et al., 1999 Gasche et al., 1999 Rosenberg and Yang, 2007), but also in hemorrhagic transformation (HT) in the setting of tissue plasminogen activator (tPA) therapy (Lapchak et al., 2000 Wang et al., 2009). At least 23 MMPs have been identified to date (Sternlicht and Werb, 2001), with MMP-2 and MMP-9 the most widely studied in stroke. MMPs are a family of zinc and calcium-dependent endopeptidases that are capable of degrading all components of the ECM including laminin, collagen and fibronectin, amongst many other targets (Van den Steen et al., 2002).
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Over the last decade the matrix metalloproteinases (MMPs) have been widely investigated for their role in disruption of the blood-brain barrier (BBB), particularly the extracellular matrix (ECM), following stroke (Romanic et al., 1998 Rosenberg et al., 1998 Fujimura et al., 1999 Gasche et al., 1999 Gidday et al., 2005) and other cerebral pathologies such as traumatic brain injury (Planas et al., 2001) and neoplasm (Lukes et al., 1999 Turba et al., 2007).