Impact of tissue plasminogen activator on the neurovascular unit: from clinical data to experimental evidence - PubMed (original) (raw)

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Impact of tissue plasminogen activator on the neurovascular unit: from clinical data to experimental evidence

Denis Vivien et al. J Cereb Blood Flow Metab. 2011 Nov.

Abstract

About 15 million strokes occur each year worldwide. As the number one cause of morbidity and acquired disability, stroke is a major drain on public health-care funding, due to long hospital stays followed by ongoing support in the community or nursing-home care. Although during the last 10 years we have witnessed a remarkable progress in the understanding of the pathophysiology of ischemic stroke, reperfusion induced by recombinant tissue-type plasminogen activator (tPA-Actilyse) remains the only approved acute treatment by the health authorities. The objective of the present review is to provide an overview of our present knowledge about the impact of tPA on the neurovascular unit during acute ischemic stroke.

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Figures

Figure 1

Figure 1

Tissue-type plasminogen activator (tPA) is a ‘JANUS' protease. tPA is a five domain serine protease including a Finger domain, an epidermal growth factor (EGF)-like domain, two kringle domains, and a catalytic domain. Pleiotropic functions of tPA as related to the specificity of each of these domains. LRP, lipoprotein receptor-related protein; PAI-1, plasminogen activator inhibitor type 1; NMDA receptor, _N_-methyl--aspartate receptor; PDGF-CC, platelet-derived growth factor-CC.

Figure 2

Figure 2

Effect of exogenous and endogenous tPA at the blood–brain barrier (BBB). (1) Tissue-type plasminogen activator (tPA)-mediated plasminogen activation promotes clot lysis and subsequent blood flow restoration. (2) tPA interacts with endothelial LRPs, leading to NF_κ_B activation and MMPs overexpression. (3) tPA can shed the ectodomain of astrocytic LRP receptors, inducing detachment of astrocytic end-feet processes. (4) tPA bound to LRP can activate latent PDGF-CC. Active PDGF-CC binds PDGF-Rα on perivascular cells leading to BBB opening. LRP, lipoprotein receptor-related protein; MMPs, metalloproteinases; PDGF-CC, platelet-derived growth factor-CC.

Figure 3

Figure 3

Tissue-type plasminogen activator (tPA) in the brain parenchyma. In the brain parenchyma, tPA, released by neurons, was reported to potentiate NMDA receptors signaling to display either neurotrophic or neurotoxic effects, to reduce apoptotic neuronal and oligodendroglial deaths, to activate microglia after binding to annexin II and LRP and to be cleared from the extracellular space by astrocytes through an LRP-dependent mechanism. LRP, lipoprotein receptor-related protein; NMDA, _N_-methyl--aspartate receptor; EGF, epidermal growth factor.

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