Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension.
BACKGROUND
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.


OBJECTIVE
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-beta. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs.


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 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.


CONCLUSIONS
PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.
Perros
Frédéric
F
Centre National de Référence de l'Hypertension Artérielle Pulmonaire, Service de Pneumologie et Réanimation Respiratoire, Institut Paris-Sud Cytokines, Hôpital Antoine-Béclère, Université Paris-Sud 11, UPRES EA 2705, Clamart, France.
Montani
David
D
Dorfmüller
Peter
P
Durand-Gasselin
Ingrid
I
Tcherakian
Colas
C
Le Pavec
Jérôme
J
Mazmanian
Michel
M
Fadel
Elie
E
Mussot
Sacha
S
Mercier
Olaf
O
Hervé
Philippe
P
Emilie
Dominique
D
Eddahibi
Saadia
S
Simonneau
Gérald
G
Souza
Rogério
R
Humbert
Marc
M
D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001549:Benzamides; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D000068877:Imatinib Mesylate; D008168:Lung / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D012333:RNA, Messenger; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor