Plasminogen Activator Mechanisms in Ischemic Stroke

Ischaemic stroke arises when a cerebral artery is occluded by a thrombus, depriving downstream tissue of oxygen and glucose. Rapid restoration of blood flow is achieved clinically by administering plasminogen activators, most commonly tissue-type plasminogen activator (tPA), which converts the zymogen plasminogen into the active protease plasmin. Plasmin selectively degrades fibrin within the clot, promoting recanalisation and salvage of ischaemic penumbra. Beyond clot dissolution, plasminogen activators interact with cellular receptors on endothelial cells, pericytes, neurons and glia, modulating the integrity of the neurovascular unit. These interactions can trigger matrix metalloproteinase activation, disrupt the blood–brain barrier and increase the risk of haemorrhagic transformation. At the same time, plasminogen activators engage signalling pathways—including Rho kinase and PDGF-CC activation—that can influence vascular permeability and astrocyte morphology. Emerging evidence also points to roles in neurovascular coupling and immune-cell mobilisation, illustrating a complex balance between therapeutic benefit and potential neurotoxic or pro-haemorrhagic effects. Optimising the efficacy and safety of plasminogen activator therapy hinges on a deeper understanding of these mechanistic pathways, narrowing the therapeutic window and reducing bleeding complications while enhancing reperfusion outcomes.

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Plasminogen Activator Mechanisms in Ischemic Stroke publication trend

The graph below shows the total number of articles in plasminogen activator mechanisms in ischemic stroke across all publications each year (not limited to Nature Index journals).

Technical terms

Plasminogen: Inactive precursor protein in plasma that is converted into plasmin by plasminogen activators.

tissue-type plasminogen activator (tPA): Endogenous serine protease used therapeutically to catalyse plasminogen activation and dissolve fibrin clots.

Thrombolysis: Process of breaking down blood clots within blood vessels, typically by pharmacological activation of plasminogen.

Blood–brain barrier (BBB): Selective endothelial interface that regulates molecular and cellular traffic between the bloodstream and the central nervous system.

Neurovascular coupling (NVC): Mechanism by which neuronal activity induces local changes in cerebral blood flow through signalling between neurons, glia and blood vessels.

Haemorrhagic transformation: Secondary bleeding into brain tissue that can occur following reperfusion therapy in ischaemic stroke, often due to BBB disruption.

References

1. Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release. Cell Death & Disease (2023).
2. Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors. Fluids and Barriers of the CNS (2023).
3. tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke. Circulation Research (2020).
4. A Review of the Mechanisms of Blood-Brain Barrier Permeability by Tissue-Type Plasminogen Activator Treatment for Cerebral Ischemia. Frontiers in Cellular Neuroscience (2016).
5. t-PA–specific modulation of a human blood-brain barrier model involves plasmin-mediated activation of the Rho kinase pathway in astrocytes. Blood (2012).
6. Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke. Acta Neuropathologica (2017).
7. Impact of Tissue Plasminogen Activator on the Neurovascular Unit: From Clinical Data to Experimental Evidence. Cerebrovascular and Brain Metabolism Reviews (2011).