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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/L979    most recent 90412.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Firth, A. L. Articles by Yuan, J. X.-J. PubMed PubMed Citation Articles by Firth, A. L. Articles by Yuan, J. X.-J.

Chronic exposure to fibrin and fibrinogen differentially regulates intracellular Ca²⁺ in human pulmonary arterial smooth muscle and endothelial cells

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 4 August 2008 ; accepted in final form 31 March 2009

Acute pulmonary embolism occurs in more than half a million people a year in the United States. Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 4% of these patients due to unresolved thromboemboli. CTEPH is thus a relatively common, progressive, and potentially fatal disease. One currently proposed theory for the poor resolution advocates that modification of fibrinogen in CTEPH patients causes resistance of emboli to fibrinolysis. The current study investigated the regulation of cytosolic Ca²⁺ ([Ca²⁺]_cyt), central to the control of cell migration, proliferation, and contraction, by chronic exposure of pulmonary artery smooth muscle (PASMC) and endothelial (PAEC) cells to fibrinogen and fibrin. Basal [Ca²⁺]_cyt was substantially elevated in PAEC after culture on fibrinogen, fibrin, and thrombin and in PASMC on fibrinogen and fibrin. In PAEC, fibrinogen significantly decreased the peak [Ca²⁺]_cyt transient (P <0.001) without a change in the transient peak width (at 50% of the peak height). This response was independent of effects on the proteinase-activated receptor (PAR) 1. Furthermore, chronic exposure to thrombin, an activator of PAR, significantly reduced the peak agonist-induced Ca²⁺ release in PAEC, but increased it in PASMC. The recovery rate of the agonist-induced [Ca²⁺]_cyt transients decelerated in PASMC chronically exposed to fibrin; a small increase of the peak Ca²⁺ was also observed. Substantial augmentation of PASMC (but not PAEC) proliferation was observed in response to chronic fibrin exposure. In conclusion, chronic exposure to fibrinogen, fibrin, and thrombin caused differential changes in [Ca²⁺]_cyt in PAEC and PASMC. Such changes in [Ca²⁺]_cyt may contribute to vascular changes in patients who have CTEPH where the pulmonary vasculature is persistently exposed to thromboemboli.

thrombin; pulmonary vascular remodeling; calcium regulation