Platelet-derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension

• Published in: American journal of respiratory and critical care medicine Vol. 178; no. 1; pp. 81 - 88
• Main Authors: Perros, Frederic, Montani, David, Dorfmuller, Peter, Durand-Gasselin, Ingrid, Tcherakian, Colas, Le Pavec, Jerome, Mazmanian, Michel, Fadel, Elie, Mussot, Sacha, Mercier, Olaf, Herve, Philippe, Emilie, Dominique, Eddahibi, Saadia, Simonneau, Gerald, Souza, Rogerio, Humbert, Marc
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01.07.2008; American Lung Association; American Thoracic Society
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Apoptosis; Apoptosis - drug effects; Benzamides; Biological and medical sciences; Blood coagulation. Blood cells; Blood platelets; Cell Count; Cell culture; Cell Movement - drug effects; Cell Proliferation - drug effects; Fundamental and applied biological sciences. Psychology; Genes; Growth factors; Humans; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Imatinib Mesylate; Intensive care medicine; Kinases; Lasers; Lung - metabolism; Lung transplants; Medical sciences; Molecular and cellular biology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Phosphorylation; Piperazines - pharmacology; Platelet; Platelet-Derived Growth Factor - metabolism; Platelet-Derived Growth Factor - pharmacology; Polymerase chain reaction; Polypeptides; Protein expression; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-sis; Pulmonary arteries; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary hypertension; Pyrimidines - pharmacology; Receptor, Platelet-Derived Growth Factor beta - metabolism; Receptors, Platelet-Derived Growth Factor - metabolism; RNA, Messenger - metabolism; Smooth muscle; Veins & arteries; France; Antineoplastic agent; Imatinib; Intensive care; remodeling; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Transferases; Idiopathic; Enzyme inhibitor; Cardiovascular disease; Smooth muscle; platelet-derived growth factor; Pulmonary hypertension; smooth muscle cells; Protein-tyrosine kinase; pulmonary arterial hypertension; Platelet derived growth factor; Resuscitation
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.200707-1037OC

Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries. To analyze the expression and pathogenic role of PDGF in idiopathic PAH. PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription-polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-beta. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs. PDGF-A, PDGF-B, PDGFR-alpha, and PDGFR-beta mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-beta in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-alpha and PDGFR-beta mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-beta. PDGF-BB-induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis. PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.