Stroke is the leading cause of morbidity and the third leading cause of mortality in the United States. Most strokes are ischemic and the majority of these are thrombotic in origin. Hemorrhagic strokes generally have worse outcomes than for ischemic strokes and hemorrhagic conversion of an ischemic stroke can markedly increase stroke severity. Thrombolytic therapy with tissue plasminogen activator (tPA) is the only approved treatment for ischemic stroke, but its use carries a significant risk for increased incidence of intracerebral hemorrhage (ICH). Thus, tPA only benefits a limited number of potential patients. The development of improved and safer therapies for stroke depends upon understanding the unique characteristics of the cerebrovasculature, and the limited benefit of tPA is due in part to its unanticipated activities in the brain beyond its well established fibrinoytic role. Several studies have demonstrated that tPA within the brain increases blood-brain-barrier (BBB) permeability after cerebral ischemia, and while there are clear benefits to some patients who receive early thrombolytic treatment, the increased risk of ICH associated with tPA demonstrate the unique challenges for its use in ischemic stroke. Ideal treatment for ischemic stroke would simultaneously promote the reestablishment of vascular patency, inhibit the development of cerebral edema, and reduce the incidence of hemorrhagic transformation. In recent studies we demonstrated that tPA within the brain activates latent platelet derived growth factor CC (PDGF- CC), which in turn increases BBB dysfunction in stroke, and that blocking this pathway significantly reduces BBB disruption, infarct size, and thrombolytic tPA induced ICH. Based on these observations, this proposal will test the hypothesis that during cerebral ischemia tPA plays a duel role, in the blood tPA promotes thrombolysis and improves reperfusion, whereas in the abluminal space tPA activates PDGF-CC which in turn promotes BBB permeability and increases the risk of ICH. We will investigate the mechanisms of this duel role of tPA, and test this hypothesis by specifically targeting tPA in blood or in the neurovascular uni (NVU), and by examining down-stream pathways regulated by PDGF-CC signaling in the NVU.

Public Health Relevance

Stroke is the leading cause of disability and the third leading cause of death in the U.S. Currently the only approved treatment for stroke, thrombolysis, carries a significant risk for bleeding in the brain, which can markedly increase stroke severity. Thus, the development of improved and safer therapies for stroke will have a major impact on U.S. public health.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
Zip Code
Carlson, Karen-Sue B; Nguyen, Lan; Schwartz, Kat et al. (2016) Neuroserpin Differentiates Between Forms of Tissue Type Plasminogen Activator via pH Dependent Deacylation. Front Cell Neurosci 10:154
Lewandowski, Sebastian A; Nilsson, Ingrid; Fredriksson, Linda et al. (2016) Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration. Acta Neuropathol 131:453-64
Su, Enming J; Fredriksson, Linda; Kanzawa, Mia et al. (2015) Imatinib treatment reduces brain injury in a murine model of traumatic brain injury. Front Cell Neurosci 9:385
Bondu, Virginie; Schrader, Ron; Gawinowicz, Mary Ann et al. (2015) Elevated cytokines, thrombin and PAI-1 in severe HCPS patients due to Sin Nombre virus. Viruses 7:559-89
Fredriksson, Linda; Stevenson, Tamara K; Su, Enming J et al. (2015) Identification of a neurovascular signaling pathway regulating seizures in mice. Ann Clin Transl Neurol 2:722-38
Wu, Jianbo; Strawn, Tammy L; Luo, Mao et al. (2015) Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-αVβ3 integrin cross talk. Arterioscler Thromb Vasc Biol 35:111-20
Zhang, Jiandong; Gu, Chunyan; Lawrence, Daniel A et al. (2014) A plasminogen activator inhibitor type 1 mutant retards diabetic nephropathy in db/db mice by protecting podocytes. Exp Physiol 99:802-15
Obi, Andrea T; Diaz, Jose A; Ballard-Lipka, Nicole L et al. (2014) Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner. J Vasc Surg Venous Lymphat Disord 2:441-450.e1
Luo, Wei; Su, Enming Joseph; Wang, Jintao et al. (2014) Increased stroke size following MCA occlusion in a mouse model of sickle cell disease. Blood 123:1965-7
Zhong, Jianyong; Yang, Hai-Chun; Kon, Valentina et al. (2014) Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts. Lab Invest 94:633-44

Showing the most recent 10 out of 19 publications