Plasmin-dependent modulation of the blood-brain barrier: a major consideration during tPA-induced thrombolysis?

Abstract

Plasmin, the principal downstream product of tissue-type plasminogen activator (tPA), is known for its potent fibrin-degrading capacity but is also recognized for many non-fibrinolytic activities. Curiously, plasmin has not been conclusively linked to blood-brain barrier (BBB) disruption during recombinant tPA (rtPA)-induced thrombolysis in ischemic stroke. This is surprising given the substantial involvement of tPA in the modulation of BBB permeability and the co-existence of tPA and plasminogen in both blood and brain throughout the ischemic event. Here, we review the work that argues a role for plasmin together with endogenous tPA or rtPA in BBB alteration, presenting the overall controversy around the topic yet creating a rational case for an involvement of plasmin in this process.

Figure 1

Proposed integrated model for tissue-type plasminogen activator (tPA)- and plasminogen (Plgn)-mediated modulation of blood–brain barrier (BBB) permeability during thrombolysis in ischemic stroke. (A) In brain endothelial cells (BECs), tPA engages low-density lipoprotein receptor (LDLR)-related protein 1 (LRP-1) (upregulated by the ischemic insult) and activates surface-bound plasminogen^, into plasmin (Pln). LRP-1 binding by tPA signals BECs to produce and secrete matrix metalloproteinase (MMP)-3 and -9.^{, ,} Plasmin activates these MMPs,^{, ,} which in turn degrade tight junctions (TJs), increasing the paracellular permeability in a process boosted by the ischemic damage to TJs. A flux of vascular tPA, plasminogen, plasmin, and activated MMPs then flows through the broken TJs and also arrives from within the injured brain, localizing on the basolateral BEC membrane, where plasmin continues to form. Subsequently, plasmin and the MMPs degrade the basement membrane (BM),^{, , ,} causing loss of BEC adhesion^, and substantial damage to the BBB. In addition, plasmin also cleaves monocyte chemoattractant protein-1 (MCP-1), an event that enhances the ability of MCP-1 to initiate Rho-kinase (ROCK) and ezrin–radixin–moesin (ERM) signaling via its receptor C-C chemokine receptor type 2 (CCR2). Activation of the ROCK and ERM pathways results in modulation of the actin cytoskeleton and BEC retraction,^{, , , ,} further enhancing TJs damage and exposure of the BM to plasmin and MMPs. Thus, the MCP-1 pathway initiates a positive feedback loop for additional loss of BEC adherence, ultimately leading to cell death and BBB impairment. (B) In astrocytes, specific tPA-mediated plasmin generation on the glial surface triggers a dual tPA-plasmin signaling events. These include tPA-induced cleavage and shedding of LRP-1, which initiates LRP-1-dependent signal, and also plasmin-mediated activation of the ROCK pathway, potentially via engagement of protease-activated receptor 1 (PAR-1).^, LRP-1 signaling and ROCK activation in turn cause modulation of the actin cytoskeleton, morphology changes and end-feet retraction in astrocytes,^{, , , , ,} leading to disruption of the BBB. Tissue-type plasminogen activator also activates platelet-derived growth factor C (PDGF-CC), which signals to astrocytes via the PDGF receptor-α (PDGFRα) to impair the BBB. It is plausible that plasmin, known for its ability to process PDGF-CC,^, may possess a similar capacity to initiate PDGF-CC-dependent BBB disruption, but this remains to be formally demonstrated.