The Neurovascular Unit

The Big Heart Disease Lie

Latest Treatment of Cardiovascular Disease

Get Instant Access

In July 2001, the National Institutes of Neurological Disorders and Stroke convened the Stroke Program Review Group (SPRG) [87] to advise on directions for basic and clinical stroke research for the following decade. Although much progress had been made in dissecting the molecular pathways of ischemic cell death, focusing therapy to a single intracellular pathway or cell type had not yielded clinically effective stroke treatment. Integrative approaches were felt to be mandatory for successful stroke therapy. This meeting emphasized the relevance of dynamic interactions between endothelial cells, vascular smooth muscle, astro- and microglia, neurons, and associated tissue matrix proteins, and gave rise to the concept of the "neurovascular unit." This modular concept emphasized the dynamics of vascular, cellular, and matrix signaling in maintaining the integrity of brain tissue within both the gray and white matter, and its importance to the pathophysiology of conditions such as stroke, vascular dementia, migraine, trauma, multiple sclerosis, and possibly the aging brain (Fig. 1.4).

The neurovascular unit places stroke in the context of an integrative tissue response in which all cel

Figure 1.4

Schematic view of the neurovascular unit or module,and some of its components.Circulating blood elements, endothelial cells, astrocytes, extracellular matrix, basal lamina, adjacent neurons, and pericytes. After ischemia, perturbations in neurovascular functional integrity initiate multiple cascades of injury.Upstream signals such as oxidative stress together with neutrophil and/or platelet interactions with activated endothelium upregulate matrix metalloproteinases (MMPs), plasminogen activators and other proteases which degrade matrix and lead to blood-brain barrier leakage. Inflammatory infiltrates through the damaged blood-brain barrier amplify brain tissue injury. Additionally, disruption of cellmatrix homeostasis may also trigger anoikis-like cell death in both vascular and parenchymal compartments. Overlaps with excitotoxicity have also been documented via t-PA-mediated interactions with the NMDA receptor that augment ionic imbalance and cell death. (t-PA Tissue plasminogen activator)

lular and matrix elements, not just neurons or blood vessels, are players in the evolution of tissue injury. For example, efficacy of the blood-brain barrier is critically dependent upon endothelial-astrocyte-matrix interactions [88]. Disruption of the neurovascular matrix, which includes basement membrane components such as type IV collagen,heparan sulfate proteoglycan, laminin, and fibronectin, upsets the cell-matrix and cell-cell signaling that maintains neurovascular homeostasis. Although many proteases including cathepsins and heparanases contribute to extracellular matrix proteolysis, in the context of stroke, plasminogen activator (PA) and MMP are probably the two most important. This is because tissue plasminogen activator (t-PA) has been used successfully as a stroke therapy, and because emerging data show important linkages between t-PA, MMPs, edema, and hemorrhage after stroke.

The MMPs are zinc endopeptidases produced by all cell types of the neurovascular unit [89], that are secreted as zymogens requiring cleavage for enzymatic activation. MMPs can be classified into gelati-nases (MMP-2 and -9),collagenases (MMP-1,-8,-13), stromelysins (MMP-3, -10, -11), membrane-type MMPs (MMP-14, -15, -16, -17), and others (e.g., MMP-7 and -12) [90]. Together with the PA system, MMPs play a central role in brain development and plasticity as they modulate extracellular matrix to allow neurite outgrowth and cell migration [91]. Upstream triggers of MMP include MAP kinase pathways [92] and oxidative stress [93]. MMP signaling is intricately linked to other well-recognized pathways after stroke, including oxidative and nitra-tive stress [94], caspase-mediated cell death [95], ex-citotoxicity, and neuro-inflammation [96,97]. Several experimental as well as human studies provide evidence for a major role of MMPs (particularly MMP-9) in ischemic stroke, primary brain hemorrhage, blood-brain barrier disruption and post-ischemic or reperfusion hemorrhage [98-106]. For example, MMP levels have been correlated with the extent of stroke as measured by diffusion- and perfusion-weighted MRI [107]. Unlike MMPs, however, there is controversy surrounding the role of the PA axis (the other major proteolytic system in mammalian brain, comprising t-PA and urokinase PA, and their inhibitors plasminogen activator inhibitor-1 and neu-roserpin) in stroke. Primary neuronal cultures genetically deficient in t-PA are resistant to oxygen-glucose deprivation [108] and t-PA knockout mice are protected against excitotoxic injury [109]. In a mouse focal ischemia model, treatment with neuroserpin reduces infarction [110]. In contrast, the responses are variable in t-PA knockouts, which are protected against focal stroke in some [111] but not other studies [112]. In part, these inconsistencies may reflect genetic differences and perhaps more importantly the balance between the clot-lysing beneficial effects of t-PA and its neurotoxic properties [113]. Emerging data suggest that administered t-PA upregulates MMP-9 via the low-density lipoprotein receptor-related protein (LRP), which avidly binds t-PA and possesses signaling properties [114]. Targeting the t-PA-LRP-MMP pathway may offer new therapeutic approaches for improving the safety profile of t-PA in patients with stroke.

Was this article helpful?

0 0
Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

Get My Free Ebook

Post a comment