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

¹ Université Paris-Sud 11, UPRES EA 2705, Centre National de Référence de l'Hypertension Artérielle Pulmonaire, Service de Pneumologie et Réanimation Respiratoire, Institut Paris-Sud Cytokines, Hôpital Antoine-Béclère, Assistance Publique Hôpitaux de Paris, Clamart, France; ² INSERM U764, Clamart, France; ³ UPRES EA 2705, Laboratoire de Chirurgie Expérimentale, Centre Chirurgical Marie Lannelongue, Université Paris-Sud 11, Le Plessis Robinson, France; and ⁴ INSERM U841 and Département de Physiologie Explorations Fonctionnelles, Hôpital Henri-Mondor, Assistance Publique Hôpitaux de Paris, Créteil, France

Correspondence and requests for reprints should be addressed to Marc Humbert, M.D., Ph.D., Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine-Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France. E-mail: marc.humbert{at}abc.aphp.fr

Rationale: 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.

Objectives: To analyze the expression and pathogenic role of PDGF in idiopathic PAH.

Methods: 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-β. The effects of imatinib on PDGF-B–induced proliferation and chemotaxis were tested on human PASMCs.

Measurements and Main Results: PDGF-A, PDGF-B, PDGFR-, and PDGFR-β 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-β 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- and PDGFR-β mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-β. PDGF-BB–induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis.

Conclusions: PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.

Key Words: imatinib • pulmonary arterial hypertension • platelet-derived growth factor • remodeling • smooth muscle cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Platelet-derived growth factor (PDGF) plays an important part in the progression of experimental pulmonary hypertension, but its role in human pulmonary arterial hypertension is only partly understood. What This Study Adds to the Field Expression of PDGF and PDGF receptors is increased in the pulmonary arteries of patients with pulmonary arterial hypertension. PDGF induces proliferation and migration of human pulmonary artery smooth muscle cells, which is inhibited by imatinib, a PDGF receptor inhibitor.

 

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