Urokinase plasminogen activator regulates pulmonary arterial contractility and vascular permeability in mice

http://www.ncbi.nlm.nih.gov/pubmed/21617202

Am J Respir Cell Mol Biol. 2011 May 26. [Epub ahead of print]
Urokinase Plasminogen Activator Regulates Pulmonary Arterial Contractility and Vascular Permeability in Mice.
Nassar T, Yarovoi S, Abu Fanne R, Waked O, Allen TC, Idell S, Cines DB, Higazi AA.
Source
Clinical Biochemistry, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Abstract
Urokinase plasminogen activator (uPA) is elevated in pathological settings such as acute lung injury where pulmonary arterial contractility and permeability are disrupted. uPA limits fibrin accretion post-injury. Here we asked whether uPA also regulates pulmonary arterial contractility and permeability. Contractility was measured using isolated pulmonary arterial rings. Pulmonary blood flow was measured in vivo by Doppler and pulmonary vascular permeability by extravasation of Evans Blue. Our data show that uPA regulates both in vitro pulmonary arterial contractility induced by phenylephrine in a dose-dependent manner through two receptor-dependent pathways and regulates vascular contractility and permeability in vivo. Physiological concentrations of uPA (≤1 nM) stimulate contractility of pulmonary arterial rings induced by phenylephrine through the LDL receptor related protein receptor (LRP). The procontractile effect of uPA is independent of its catalytic activity. At pathophysiological concentrations, uPA (20 nM) inhibits contractility and increases vascular permeability. Inhibition of vascular contractility and increase of vascular permeability is mediated through a two-step process that involves docking to N-methyl-D-aspartate (NMDA) receptor-1 (NMDA-R1) on pulmonary vascular smooth muscle cells and requires catalytic activity. Peptides that specifically inhibit uPA docking to NMDA-R or a uPA variant with a mutated receptor docking site abolished both its effects on vascular contractility and permeability without affecting its catalytic activity. These data show that uPA, at concentrations found in pathological conditions, reduces pulmonary arterial contractility and increases permeability though activation of NMDA-R1. Selective inhibition of NMDAR-1 activation by uPA can be accomplished without loss of fibrinolytic activity.