tPA regulates pulmonary vascular activity through NMDA receptors

Taher Nassar, Khalil Bdeir, Serge Yarovoi, Rami Abu Fanne, Juan Carlos Murciano, Steven Idell, Timothy Craig Allen, Douglas B. Cines, Abd Al Roof Higazi

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Tissue-type plasminogen activator (tPA) is a potent fibrinolytic enzyme used to treat acute coronary artery obstruction. However, tPA has shown limited utility in other disorders caused by thrombotic vascular occlusion, such as pulmonary embolism. We found that tPA caused dose-dependent effects on the contractility of pulmonary arterial rings that may affect its effectiveness as a thrombolytic agent. At low concentrations (1 nM), tPA stimulated pulmonary vascular contraction in response to phenylephrine, whereas at higher concentrations (20 nM) tPA inhibited pulmonary arterial contractility and promoted pulmonary vascular permeability through an interaction between its "docking site" and N-methyl d-aspartate receptor type 1 (NMDA-R1) expressed by pulmonary arteries. A hexapeptide derived from plasminogen activator inhibitor type 1 that blocked the docking site of tPA, but not its catalytic activity, inhibited its interaction with NMDA-R1, abolished inhibition of pulmonary artery contractility, attenuated vascular permeability, and facilitated fibrinolysis in a murine model of pulmonary embolism. Similar outcomes were seen using a tPA variant that lacks the docking site but retains catalytic activity. These data suggest that it is feasible to attenuate the deleterious extrafibrinolytic effects of tPA and improve its benefit:risk profile in the management of pulmonary embolism.

Original languageEnglish (US)
Pages (from-to)L307-L314
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume301
Issue number3
DOIs
StatePublished - Sep 1 2011

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Keywords

  • Fibrinolytic enzymes
  • N-methyl-D-aspartate
  • Plasminogen activators
  • Pulmonary emboli
  • Tissue-type plasminogen activator

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Nassar, T., Bdeir, K., Yarovoi, S., Fanne, R. A., Murciano, J. C., Idell, S., Allen, T. C., Cines, D. B., & Higazi, A. A. R. (2011). tPA regulates pulmonary vascular activity through NMDA receptors. American Journal of Physiology - Lung Cellular and Molecular Physiology, 301(3), L307-L314. https://doi.org/10.1152/ajplung.00429.2010