Angiopoietin/Tie2 Pathway Influences Smooth Muscle Hyperplasia in Idiopathic Pulmonary Hypertension

• Published in: American journal of respiratory and critical care medicine Vol. 174; no. 9; pp. 1025 - 1033
• Main Authors: Dewachter, Laurence, Adnot, Serge, Fadel, Elie, Humbert, Marc, Maitre, Bernard, Barlier-Mur, Anne-Marie, Simonneau, Gerald, Hamon, Michel, Naeije, Robert, Eddahibi, Saadia
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01-11-2006; American Lung Association; American Thoracic Society
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Angiopoietin-1 - physiology; Arterial hypertension. Arterial hypotension; Aspartic Acid Endopeptidases - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Blood platelets; Blotting, Western; Cardiology. Vascular system; Cell growth; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Endothelial Cells - physiology; Endothelin-1 - metabolism; Endothelin-Converting Enzymes; Endothelium; Endothelium, Vascular - cytology; Enzymes; Epidermal growth factor; Female; Fluoxetine - pharmacology; Humans; Hyperplasia; Hypertension, Pulmonary - physiopathology; Immunohistochemistry; Intensive care medicine; Kinases; Lungs; Male; Medical sciences; Metalloendopeptidases - metabolism; Muscle, Smooth, Vascular - physiopathology; Pneumology; Pulmonary arteries; Pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Receptor, TIE-2; Serotonin; Serotonin Uptake Inhibitors - pharmacology; Smooth muscle; Veins & arteries; France; Germany; angiopoietin-1; Endothelial cell; Intensive care; growth factors; Respiratory disease; Hyperplasia; Idiopathic; Cardiovascular disease; Smooth muscle; Pulmonary artery; Pulmonary hypertension; idiopathic pulmonary arterial hypertension; pulmonary endothelial cells; Pulmonary vessel; Blood vessel; pulmonary artery smooth muscle; Circulatory system; Resuscitation; Growth factor
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200602-304OC

Angiopoietins are involved in blood vessel maturation and remodeling.
One consequence of endothelium-specific tyrosine kinase-2 (Tie2) receptor activation by angiopoietin-1 (Ang1) is the release of endothelium-derived growth factors that recruit vascular wall cells. We investigated this process in idiopathic pulmonary arterial hypertension (iPAH).
Ang1, Ang2, and total and phosphorylated Tie2 expression (mRNA and protein) was evaluated in human lung specimens and in cultured pulmonary artery smooth muscle cells (PA-SMCs) and pulmonary endothelial cells (P-ECs) isolated from patients with iPAH and control subjects. Media collected from Ang1-treated P-ECs were assessed for their PA-SMC growth-promoting effect.
Tie2 receptor was fourfold higher in lungs and P-ECs from patients with iPAH than in those from control subjects, with a parallel increase in phosphorylated lung Tie2 receptor. In contrast, Ang1 and Ang2 expression in lungs, P-ECs, and PA-SMCs did not differ. Incubation of PA-SMCs with medium collected from P-EC cultures induced marked proliferation, and this effect was stronger when using P-ECs from patients with iPAH than from control subjects. Ang1 pretreatment of P-ECs from either patients or control subjects induced a further increase in PA-SMC proliferation. Fluoxetine, an inhibitor of the mitogenic action of serotonin, reduced the growth-promoting effect of P-EC media. Ang1 added to P-ECs from patients with iPAH increased the production of endothelin-1 (ET-1) and serotonin, but not of platelet-derived growth factor-BB or epidermal growth factor, and increased the amount of mRNA encoding tryptophan hydroxylase-1 (the rate-limiting enzyme of serotonin synthesis), preproET-1, and ET-1-converting enzyme.
The Ang1/Tie2 pathway is potentiated in iPAH, contributing to PA-SMC hyperplasia via increased stimulation of endothelium-derived growth factors synthesis by P-ECs.