title: tPA regulates pulmonary vascular activity through NMDA receptors.
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.
authors.affiliation: Dept. of Pathology and Laboratory Medicine, Univ. of Pennsylvania, 513A Stellar-Chance, 422 Curie Blvd., Philadelphia, PA 19104, USA.
authors.forename: Taher
authors.initials: T
authors.lastname: Nassar
authors.forename: Khalil
authors.initials: K
authors.lastname: Bdeir
authors.forename: Serge
authors.initials: S
authors.lastname: Yarovoi
authors.forename: Rami Abu
authors.initials: RA
authors.lastname: Fanne
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Murciano
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
authors.forename: Timothy Craig
authors.initials: TC
authors.lastname: Allen
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011655:Pulmonary Embolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D010656:Phenylephrine; D010959:Tissue Plasminogen Activator