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1.
Transl Stroke Res ; 13(5): 801-815, 2022 10.
Article in English | MEDLINE | ID: mdl-35122213

ABSTRACT

Tissue plasminogen activator (tPA) is a multifunctional protease. In blood tPA is best understood for its role in fibrinolysis, whereas in the brain tPA is reported to regulate blood-brain barrier (BBB) function and to promote neurodegeneration. Thrombolytic tPA is used for the treatment of ischemic stroke. However, its use is associated with an increased risk of hemorrhagic transformation. In blood the primary regulator of tPA activity is plasminogen activator inhibitor 1 (PAI-1), whereas in the brain, its primary inhibitor is thought to be neuroserpin (Nsp). In this study, we compare the effects of PAI-1 and Nsp deficiency in a mouse model of ischemic stroke and show that tPA has both beneficial and harmful effects that are differentially regulated by PAI-1 and Nsp. Following ischemic stroke Nsp deficiency in mice leads to larger strokes, increased BBB permeability, and increased spontaneous intracerebral hemorrhage. In contrast, PAI-1 deficiency results in smaller infarcts and increased cerebral blood flow recovery. Mechanistically, our data suggests that these differences are largely due to the compartmentalized action of PAI-1 and Nsp, with Nsp deficiency enhancing tPA activity in the CNS which increases BBB permeability and worsens stroke outcomes, while PAI-1 deficiency enhances fibrinolysis and improves recovery. Finally, we show that treatment with a combination therapy that enhances endogenous fibrinolysis by inhibiting PAI-1 with MDI-2268 and reduces BBB permeability by inhibiting tPA-mediated PDGFRα signaling with imatinib significantly reduces infarct size compared to vehicle-treated mice and to mice with either treatment alone.


Subject(s)
Cerebral Hemorrhage , Ischemic Stroke , Neuropeptides , Plasminogen Activator Inhibitor 1 , Serpins , Animals , Blood-Brain Barrier , Cerebral Hemorrhage/chemically induced , Cerebral Hemorrhage/drug therapy , Hemorrhagic Disorders , Mice , Neuropeptides/metabolism , Plasminogen Activator Inhibitor 1/deficiency , Plasminogen Activator Inhibitor 1/metabolism , Serpins/metabolism , Tissue Plasminogen Activator/adverse effects , Neuroserpin
2.
Acta Neuropathol ; 134(4): 585-604, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28725968

ABSTRACT

Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood-brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα). However, in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted microglia throughout), acts together with the endocytic receptor LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1-/-) are protected from tPA-induced BBB permeability but not from permeability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRα all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1-/- mice show significantly less PDGFRα phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b+ cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1-/- mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRα signaling in the NVU and controlling BBB permeability.


Subject(s)
Blood-Brain Barrier/metabolism , Brain Ischemia/metabolism , Capillary Permeability/physiology , Lymphokines/metabolism , Microglia/metabolism , Platelet-Derived Growth Factor/metabolism , Stroke/metabolism , Animals , Arterioles/drug effects , Arterioles/metabolism , Arterioles/pathology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/pathology , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Brain Ischemia/drug therapy , Brain Ischemia/pathology , CD11b Antigen/metabolism , Capillary Permeability/drug effects , Cells, Cultured , Cerebral Hemorrhage/chemically induced , Cerebral Hemorrhage/metabolism , Cerebral Hemorrhage/pathology , Disease Models, Animal , Female , Fibrinolytic Agents/adverse effects , Fibrinolytic Agents/pharmacology , Leukocytes/metabolism , Leukocytes/pathology , Low Density Lipoprotein Receptor-Related Protein-1 , Macrophage-1 Antigen/genetics , Macrophage-1 Antigen/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Microglia/pathology , Receptors, LDL/metabolism , Stroke/drug therapy , Stroke/pathology , Tissue Plasminogen Activator/adverse effects , Tissue Plasminogen Activator/pharmacology , Tumor Suppressor Proteins/metabolism
4.
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