Published ahead of print on August 17, 2006, doi:10.1164/rccm.200602-304OC Am. J. Respir. Crit. Care Med., Volume 174, Number 9, November 2006, 1025-1033 A more recent version of this article appeared on November 1, 2006
Submitted on February 28, 2006 Angiopoietin/Tie2 Pathway Influences Smooth Muscle Hyperplasia in Idiopathic Pulmonary HypertensionLaurence Dewachter1*,1 Departement de Physiologie, INSERM U651, Hopital H. Mondor, AP-HP, Creteil, France, 2 Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, UPRES EA2705, Hopital Marie Lannelongue, Le Plessis Robinson, France, 3 Service de Pneumologie, Hopital Antoine Beclere, Clamart, France, 4 NeuroPsychoPharmacologie, Faculte de Medecine Pitie-Salpetriere, UMR 677 INSERM/UPMC, Paris, France, 5 Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium * To whom correspondence should be addressed. E-mail: dewachter{at}creteil.inserm.fr.
Rationale: Angiopoietins are involved in blood-vessel maturation and remodeling. Objectives: One consequence of endothelial-specific receptor Tie2 activation by angiopoietin-1 (Ang1) is the release of endothelial-derived growth factors that recruit vascular wall cells. We investigated this process in idiopathic pulmonary arterial hypertension (iPAH). Methods: Ang1, Ang2, total and phosphorylated Tie2 expressions (mRNA and protein) were evaluated in human lung specimens and in cultured pulmonary smooth muscle (PA-SMCs) and endothelial cells (P-ECs) isolated from iPAH patients and controls. Media collected from Ang1-treated P-ECs were assessed for their PA-SMC growth promoting effect. Measurements and Main Results: Tie2 receptor was 4-fold higher in lungs and P-ECs from iPAH patients than in those from controls, with a parallel increase in phosphorylated lung Tie2 receptor. In contrast, Ang1 and Ang2 expression in lungs, P-ECs and PA-SMCs didn't differ. Incubation of PA-SMCs with medium collected from P-EC cultures induced marked proliferation, and this effect was stronger using P-ECs from patients with iPAH than from controls. Ang1 pretreatment of P-ECs from either patients or controls induced a further increase in PA-SMC proliferation. Fluoxetine, an inhibitor of mitogenic action of serotonin, reduced growth-promoting effect of P-EC media. Ang1 added to P-ECs from iPAH patients increased the production of endothelin-1 (ET-1) and serotonin, but not of PDGF-BB or EGF, and increased the amount of mRNA encoding tryptophan-hydroxylase1 (TPH1, the rate-limiting enzyme of serotonin synthesis), preproET-1, and ET-1 converting enzyme. Conclusions: Ang1/Tie2 pathway is potentiated in iPAH, contributing to PA-SMC hyperplasia via increased stimulation of endothelium-derived growth factors synthesis by P-ECs. Key words: Idiopathic pulmonary arterial hypertension, angiopoietin-1, pulmonary artery smooth muscle, pulmonary endothelial cells, growth factors
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