Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia.
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.


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.
Eddahibi
Saadia
S
INSERM U651, Département de Physiologie, Hôpital H. Mondor, AP-HP, Créteil, france. saadia.eddahibi@creteil.inserm.fr
Guignabert
Christophe
C
Barlier-Mur
Anne-Marie
AM
Dewachter
Laurence
L
Fadel
Elie
E
Dartevelle
Philippe
P
Humbert
Marc
M
Simonneau
Gerald
G
Hanoun
Naïma
N
Saurini
Françoise
F
Hamon
Michel
M
Adnot
Serge
S
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000737:chemistry / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D016895:Culture Media, Serum-Free; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D014365:Tryptophan Hydroxylase