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Published ahead of print on April 17, 2008, doi:10.1164/rccm.200707-1037OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 1, July 2008, 81-88

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Submitted on July 14, 2007
Accepted on April 15, 2008

Platelet Derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension

Frederic Perros1, David Montani2, Peter Dorfmuller2, Ingrid Durand-Gasselin3, Colas Tcherakian2, Jerome Le Pavec4, Michel Mazmanian5, Elie Fadel5, Sacha Mussot5, Olaf Mercier5, Philippe Herve5, Dominique Emilie3, Saadia Eddahibi6, Gerald Simonneau4, Rogerio Souza2, and Marc Humbert2*

1 Service de Pneumologie et Reanimation Respiratoire, Universite Paris-Sud 11, UPRES EA 2705, Centre National de Reference de l'Hypertension Arterielle Pulmonaire, Institut Paris-Sud Cytokines, Hopital Antoine-Beclere, Assistance Publique Hopitaux de Paris, Clamart, France; UPRES EA 2705, Laboratoire de Chirurgie Experimentale, Centre Chirurgical Marie Lannelongue, Universite Paris-Sud 11, Le Plessis Robinson, France, 2 Service de Pneumologie et Reanimation Respiratoire, Universite Paris-Sud 11, UPRES EA 2705, Centre National de Reference de l'Hypertension Arterielle Pulmonaire, Institut Paris-Sud Cytokines, Hopital Antoine-Beclere, Assistance Publique Hopitaux de Paris, Clamart, France; INSERM U764, Clamart, France, 3 INSERM U764, Clamart, France, 4 Service de Pneumologie et Reanimation Respiratoire, Universite Paris-Sud 11, UPRES EA 2705, Centre National de Reference de l'Hypertension Arterielle Pulmonaire, Institut Paris-Sud Cytokines, Hopital Antoine-Beclere, Assistance Publique Hopitaux de Paris, Clamart, France, 5 UPRES EA 2705, Laboratoire de Chirurgie Experimentale, Centre Chirurgical Marie Lannelongue, Universite Paris-Sud 11, Le Plessis Robinson, France, 6 Departement de Physiologie Explorations Fonctionnelles, INSERM U841, Hopital Henri- Mondor, Assistance Publique Hopitaux de Paris, Creteil, France

* To whom correspondence should be addressed. 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 (PASMC), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMC 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 receptors 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 PASMC. Measurements and Main Results: PDGF-A, PDGF-B, PDGFR-{alpha} and PDGFR-{beta} mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared to controls. 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 -B mainly localized to PASMC and endothelial cells ((perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-{alpha} and -{beta} mainly stained PASMC and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated-PDGFR-{beta}. PDGF-BB-induced proliferation and migration of PASMC 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, PDGF, Remodeling, Smooth muscle cells




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