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(Circulation. 2006;113:1857-1864.)
© 2006 American Heart Association, Inc.

Hypertension

Cross Talk Between Endothelial and Smooth Muscle Cells in Pulmonary Hypertension

Critical Role for Serotonin-Induced Smooth Muscle Hyperplasia

Saadia Eddahibi, PhD; Christophe Guignabert, PhD; Anne-Marie Barlier-Mur, BS; Laurence Dewachter, MS; Elie Fadel, MD; Philippe Dartevelle, MD; Marc Humbert, MD; Gerald Simonneau, MD; Naïma Hanoun, MS; Françoise Saurini, MS; Michel Hamon, PhD; Serge Adnot, MD

From INSERM U651 and Département de Physiologie, Hôpital H. Mondor, AP-HP, Créteil (S.E., C.G., M.-M.B.-M., L.D., S.A.); UMR 677 INSERM/UPMC, NeuroPsychoPharmacologie, Faculté de Médecine Pitié-Salpêtrière, Paris (N.H., F.S., M.H.); Service de Pneumologie, Hôpital A. Béclère, AP-HP, Clamart (M.H., G.S.); and UPRES EA2705, Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Hôpital Marie Lannelongue, Le Plessis Robinson (E.F., P.D.), France.

Correspondence to Saadia Eddahibi, INSERM U651, Faculté de Médecine, 8 Rue du Général Sarrail, 94010 Créteil, France. E-mail saadia.eddahibi{at}creteil.inserm.fr

Received September 28, 2005; revision received February 8, 2006; accepted February 9, 2006.

Background— The mechanism of pulmonary artery smooth muscle cell (PA-SMC) hyperplasia in idiopathic pulmonary artery hypertension (iPH) may involve both an inherent characteristic of PA-SMCs and abnormal control by external stimuli. We investigated the role of pulmonary microvascular endothelial cells (P-ECs) in controlling PA-SMC growth.

Methods and Results— Serum-free medium of quiescent P-ECs elicited marked PA-SMC proliferation, and this effect was greater with P-ECs from patients with iPH than from control subjects and greater with PA-SMCs from these patients than from control subjects. Fluoxetine, which inhibits serotonin-induced mitogenesis by blocking the serotonin transporter, and p-chlorophenylalanine, which inhibits serotonin synthesis by blocking tryptophan hydroxylase (TPH), caused a similar 60% reduction in the growth-promoting effect of P-EC media, whereas endothelin receptor blockers had no effect. Assays of TPH activity in P-EC medium based on p-chlorophenylalanine–sensitive 5-hydroxytryptophan accumulation or serotonin determination indicated serotonin synthesis by P-ECs and an increase in this TPH-dependent process in iPH. Expression of the tph1 gene encoding the peripheral form of the TPH enzyme was increased in lungs and P-ECs from patients with iPH. Lung TPH1 immunostaining was confined to the pulmonary vessel intima.

Conclusions— P-ECs produce paracrine factors governing PA-SMC growth. Serotonin, the main P-EC–derived growth factor, is overproduced in iPH and contributes to PA-SMC hyperplasia.

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