Published Online
on April 10, 2006

A more recent version of this article appeared on April 18, 2006

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Submitted on September 28, 2005
Revised on February 8, 2006
Accepted on February 9, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: saadia.eddahibi{at}creteil.inserm.fr.

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.

Key words: endothelial cells • hypertension, pulmonary • serotonin • tryptophan hydroxylase

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